Oxopiperazine derivatives

ABSTRACT

The present invention relates to novel compounds of formula (I) or formula (Ia) 
     
       
         
         
             
             
         
       
     
     pharmaceutically-acceptable salts, hydrates, solvates, or stereoisomers thereof, and pharmaceutical compositions of these compounds which are useful for preventive and therapeutic use in human and veterinary medicine.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to, and the benefit of U.S. ApplicationNo. 62/599,336, filed Dec. 15, 2017 and Swiss Application No. 1522018,filed Feb. 8, 2018, the entire contents of each of which areincorporated herein by reference.

INCORPORATION OF THE SEQUENCE LISTING

The contents of the text file named “NTHR-001-001WO_SeqList” which wascreated on Dec. 12, 2018 and is 32 KB in size are hereby incorporated byreference in their entirety.

FIELD OF THE INVENTION

The present invention relates to novel compounds of formula (I) orformula (Ia):

pharmaceutically-acceptable salts, hydrates, solvates, or stereoisomersthereof, and pharmaceutical compositions of these compounds which areuseful for preventive and therapeutic use in human and veterinarymedicine.

BACKGROUND

Despite the ever increasing number of cancer therapies in general, andcombination cancer therapies in particular, cancer is still the thirdmost common cause of death worldwide after cardiovascular diseases andinfectious/parasitic diseases; in absolute numbers, this corresponds to7.6 million deaths (ca. 13% of all deaths) in any given year. The WorldHealth Organization (WHO) estimates deaths due to cancer to increase to13.1 million by 2030, while the American Cancer Society expects over1,685,210 new cancer cases diagnosed and 595,690 cancer deaths in theU.S. in 2016. A 2012 survey by McMillan Cancer Support in the U.K. hasrevealed that the median survival time of cancer patients overall hasincreased from 1 year to 6 years since the 1970s. However, for manycancers including esophageal-, stomach-, lung-, brain- and pancreaticcancer, median survival has barely improved, remaining less than oneyear.

These statistics illustrate the fact that cancer remains a criticalhealth condition and that there is an urgent need for new anticancerdrugs.

SUMMARY

The present invention relates to novel compounds of formula (Ia). Thepresent invention provides novel compounds according to formula (Ia):

or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein:

R¹ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by cycloalkyl,aryl or heteroaryl, wherein the cycloalkyl, aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R² is selected from H, C(O)R¹⁴, C(O)NR¹⁵R¹⁵, C(O)OR¹⁵, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₅alkyl-OR⁸, C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₅alkyl-NHCOR¹³, or C₁₋₃ alkyl substituted by cycloalkyl, aryl orheteroaryl, wherein the cycloalkyl, aryl or the heteroaryl is optionallysubstituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; with the provisothat when R² is C(O)NR¹⁵R¹⁵, both R¹⁵ can form a ring wherein the ringcontains the N of NR¹⁵R¹⁵ and optionally one further heteroatom selectedfrom O and N, wherein if the one further heteroatom is N, it isoptionally substituted by R⁸;

R³ and R⁷ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl, alloptionally substituted by halogen, OR⁸, NR⁸R¹¹, or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁴ is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by cycloalkyl,aryl or heteroaryl, wherein the cycloalkyl, aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁵ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, C₁₋₃ alkyl-OR⁸, or SR⁸; and whereinR⁵ can form a ring with any part of X or Y, wherein the ring optionallycontains a carbonyl group;

R⁶ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloakenyl, all optionally substituted by halogen,OR⁸, NR⁸R¹¹; C₁₋₃ alkyl substituted by C(O)NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; andwherein R⁶ can form a ring with any part of X; or is imidazolidinone;

R⁸ and R¹¹ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl;

X is selected from a bond, C₁₋₇ alkanediyl, C₂₋₇ alkenediyl, C₂₋₇alkynediyl, C₃₋₉ cycloalkanediyl, C₄₋₆ cycloalkenediyl, —O—, C₁₋₃alkanediyl-O—, —O—C₁₋₇ alkanediyl, —O—C₃₋₉ cycloalkanediyl, C₁₋₃alkanediyl-O—C₁₋₇ alkanediyl, C₁₋₇ heteroalkanediyl, or —S—C₁₋₇alkanediyl; and wherein X can form a ring or a polycyclic system withany part of R⁵, R⁶, or Y, wherein the ring optionally contains acarbonyl group;

Y is selected from H, C(O)NR¹⁰R¹², C(O)OR¹⁰, R¹¹NC(O)NR¹¹R¹², OC(O)R¹⁰,OC(O)NR¹¹R¹², S(O)_(n)R⁸ wherein n is 0, 1 or 2, SO₂NR¹⁰R¹², NR¹⁰SO₂R¹⁰,NR¹⁰R¹², HNCOR⁸, CN, C₃₋₇-cycloalkyl optionally containing a heteroatomin the ring selected from O and N wherein if the heteroatom is N it isoptionally substituted by R⁸; S-aryl, O-aryl, S-heteroaryl, O-heteroarylwherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionallysubstituted by one or more R⁹ or R¹⁴; or aryl, heteroaryl wherein thearyl or heteroaryl is optionally substituted by one or more of R⁸; andwherein Y can form a ring with any part of X or R⁵, wherein the ringoptionally contains a carbonyl group; with the proviso that when Y isC(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² can form a ring wherein the ringcontains the N of NR¹⁰R¹² and optionally one further heteroatom selectedfrom O and N, wherein if the one further heteroatom is N, it isoptionally substituted by R⁸;

R⁹ is selected from H, halogen, C₁₋₅ alkyl, C₂₋₅ alkenyl, C₂₋₅ alkynyl,C₃₋₅ cycloalkyl, C₁₋₅ alkyl-OR⁸, C₁₋₅ alkyl-SR⁸, C₁₋₅ alkyl-NR⁸R¹¹, C₁₋₅alkyl-C(O)OR⁸, C₁₋₅ alkyl-C(O)NR⁸R¹¹, C₁₋₅ alkyl-C(O)R¹⁰, CN, C(O)R⁸,C(O)NR⁸R¹¹, C(O)OR⁸, NR⁸C(O)NR⁸R¹¹, OC(O)NR⁸R¹¹, SO₂NR⁸R¹¹, NR⁸SO₂R⁸,OR⁸, NR⁸R¹¹, or S(O)_(n)R⁸ wherein n is 0, 1 or 2;

R¹⁰ and R¹² are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₃alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₃ alkyl-aryl, or C₁₋₃alkyl-heteroaryl, all these groups optionally substituted by halogen,OR⁸, or NR⁸R¹¹;

R¹³ is C₁₋₅ alkyl substituted by a bicyclic ring optionally containingat least one heteroatom and a carbonyl group;

R¹⁴ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; and

each R¹⁵ is independently selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, or C₁₋₃alkyl-OR⁸.

In another aspect, the present invention relates to novel compounds offormula (I). The present invention provides novel compounds according toformula (I):

or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein:

R¹ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R² is selected from H, C(O)R¹⁴, C(O)NR¹⁵R¹⁵, C(O)OR¹⁵, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₅alkyl-OR⁸, C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₅alkyl-NHCOR¹³, or C₁₋₃ alkyl substituted by aryl or heteroaryl, whereinthe aryl or the heteroaryl is optionally substituted by halogen, C₁₋₄alkyl or C₃₋₅ cycloalkyl; with the proviso that when R² is C(O)NR¹⁵R¹⁵,both R¹⁵ can form a ring wherein the ring contains the N of NR¹⁵R¹⁵ andoptionally one further heteroatom selected from O and N, wherein if theone further heteroatom is N, it is optionally substituted by R⁸;

R³ and R⁷ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, alloptionally substituted by halogen, OR⁸, NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁴ is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁵ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, C₁₋₃ alkyl-OR⁸, or SR⁸; and whereinR⁵ can form a ring with any part of X or Y, wherein the ring optionallycontains a carbonyl group;

R⁶ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, all optionally substituted by halogen,OR⁸, NR⁸R¹¹; or C₁₋₃ alkyl substituted by C(O)NR⁸R¹¹; C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; or isimidazolidinone;

R⁸ and R¹¹ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl;

X is selected from a bond, C₁₋₇ alkanediyl, C₂₋₇ alkenediyl, C₂₋₇alkynediyl, C₃₋₆ cycloalkanediyl, C₄₋₆ cycloalkenediyl, —O—, C₁₋₃alkanediyl-O—, —O—C₁₋₇ alkanediyl, C₁₋₃ alkanediyl-O—C₁₋₇ alkanediyl,C₁₋₇ heteroalkanediyl, or —S—C₁₋₇ alkanediyl; and wherein X can form aring with any part of R⁵ or Y, wherein the ring optionally contains acarbonyl group;

Y is selected from H, C(O)NR¹⁰R¹², C(O)OR¹⁰, R¹¹NC(O)NR¹¹R¹², OC(O)R¹⁰,OC(O)NR¹⁰R¹², S(O)_(n)R⁸ wherein n is 0, 1 or 2, SO₂NR¹⁰R¹², NR¹⁰SO₂R¹⁰,NR¹⁰R¹², HNCOR⁸, CN, C₃₋₇-cycloalkyl optionally containing a heteroatomin the ring selected from O and N wherein if the heteroatom is N it isoptionally substituted by R⁸; S-aryl, O-aryl, S-heteroaryl, O-heteroarylwherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionallysubstituted by one or more R⁹ or R¹⁴; aryl, or heteroaryl wherein thearyl or heteroaryl is optionally substituted by one or more of R⁸; andwherein Y can form a ring with any part of X or R⁵, wherein the ringoptionally contains a carbonyl group; with the proviso that when Y isC(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² can form a ring wherein the ringcontains the N of NR¹⁰R¹² and optionally one further heteroatom selectedfrom O and N, wherein if the one further heteroatom is N, it isoptionally substituted by R⁸;

R⁹ is selected from H, halogen, C₁₋₅ alkyl, C₂₋₅ alkenyl, C₂₋₅ alkynyl,C₃₋₅ cycloalkyl, C₁₋₅ alkyl-OR⁸, C₁₋₅ alkyl-SR⁸, C₁₋₅ alkyl-NR⁸R¹¹, C₁₋₅alkyl-C(O)OR⁸, C₁₋₅ alkyl-C(O)NR⁸R¹¹, C₁₋₅ alkyl-C(O)R¹⁰, CN, C(O)R⁸,C(O)NR⁸R¹¹, C(O)OR⁸, NR⁸C(O)NR⁸R¹¹, OC(O)NR⁸R¹¹, SO₂NR⁸R¹¹, NR⁸SO₂R⁸,OR⁸, NR⁸R¹¹, or S(O)_(n)R⁸ wherein n is 0, 1 or 2;

R¹⁰ and R¹² are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₃alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₃ alkyl-aryl, or C₁₋₃alkyl-heteroaryl, all these groups optionally substituted by halogen,OR⁸, or NR⁸R¹¹;

R¹³ is C₁₋₅ alkyl substituted by a bicyclic ring optionally containingat least one heteroatom and a carbonyl group;

R¹⁴ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; and

each R¹⁵ is independently selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, or C₁₋₃alkyl-OR⁸.

The present invention also relates to pharmaceutical compositions usefulfor preventive and therapeutic use in human and veterinary medicinecomprising compounds of the formula (I) and/or formula (Ia) andpharmaceutically-acceptable salts, hydrates, solvates, or stereoisomersthereof. The present invention is useful in methods for preventing andtreating cancer.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. In the specification, thesingular forms also include the plural unless the context clearlydictates otherwise. Although methods and materials similar or equivalentto hose described herein can be used in the practice or testing of thepresent disclosure, suitable methods and materials are described below.All publications, patent applications, patents and other referencesmentioned herein are incorporated by reference. The references citedherein are not admitted to be prior art to the claimed invention. In thecase of conflict, the present specification, including definitions, willcontrol. In addition, the materials, methods and examples areillustrative only and are not intended to be limiting. In the case ofconflict between the chemical structures and names of compoundsdisclosed herein, the chemical structures will control.

Other features and advantages of the disclosure will be apparent fromthe following detailed description and claims.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph showing tumor growth inhibition in a patient-derivedxenograft model of head and neck cancer. NMRI nude mice bearing HN11873subcutaneous tumors were treated p.o. BID with either vehicle (control)or 30 mg/kg test Compound 57.

FIG. 2A-2F are graphs depicting characteristic 5-day cell proliferationinhibition curves. The figure shows the inhibition curves for the valuesreported for lymphoma cell lines and Compound 258 (light gray line) inTABLE 5. Concentrations are given in micromol/lt (μM), T₀=day 0 reading(proliferation reference). The cisplatin (quality control) inhibitioncurve is shown in dark grey.

FIG. 3 is a graph showing the tumor size development in acastration-resistant patient-derived xenograft mouse model of prostatecancer at various concentrations of Compound 258 and Compound 284,compared to standard-of-care treatment (Enzalutamide). The arrowindicates a concentration switch from Compound 258 10 mg/kg to 3 mg/kgat day 51.

FIG. 4 is a graph showing mice body weight development in acastration-resistant patient-derived xenograft mouse model of prostatecancer at various concentration of Compound 258 and Compound 284,compared to standard-of-care treatment (Enzalutamide). The arrowindicates a concentration switch from Compound 258 10 mg/kg to 3 mg/kgat day 51.

FIG. 5 is a graph showing tumor size development in a hormone-resistantcell-derived xenograft mouse model of prostate cancer (DU-145 cells) atvarious concentrations of Compound 258, Compound 279, Compound 253 andCompound 284.

FIG. 6 is a graph showing mice body weight development in ahormone-resistant cell-derived xenograft mouse model of prostate cancer(DU-145 cells) at various concentrations of Compound 258, Compound 279,Compound 253 and Compound 284.

FIG. 7 is a graph showing tumor size development in a colorectal cancercell-derived xenograft mouse model (HCT116 cells) at variousconcentrations of Compound 258, Compound 279 and Compound 284, comparedto standard-of-care treatment (Avastin, also called bevacizumab).

FIG. 8 is a graph showing mice body weight development in a colorectalcancer cell-derived xenograft mouse model (HCT116 cells) at variousconcentrations of Compound 258, Compound 279 and Compound 284, comparedto standard-of-care treatment (Avastin).

FIG. 9 is a graph showing the tumor size development in a gastric cancercell-derived xenograft mouse model (MKN45 cells) at variousconcentrations of Compound 258, Compound 253 and Compound 284, comparedto standard-of-care treatment (Paclitaxel).

FIG. 10 is a graph showing mice body weight development in a gastriccancer cell-derived xenograft mouse model (MKN45 cells) at variousconcentrations of Compound 258, Compound 253 and Compound 284, comparedto standard-of-care treatment (Paclitaxel).

FIG. 11 is a graph showing tumor size development in an HPV-positivecervical cancer cell-derived xenograft mouse model (SiHa cells) atvarious concentrations of Compound 248, Compound 273, Compound 318 andCompound 258.

FIG. 12 is a graph showing mice body weight development in anHPV-positive cervical cancer cell-derived xenograft mouse model (SiHacells) at various concentrations of Compound 248, Compound 273, Compound318 and Compound 258.

FIGS. 13A and 13B are graphs showing luciferase activity in a MOLM13-Lucmouse model for acute myeloid leukemia tumor spread. (A) Mean in vivoluciferase activity (photons/s) profile (whole body imaging): testcompound is Compound 258, administered at 1, 3 and 6 mg/kg, displayedversus the corresponding vehicle control group. Data are displayed asmean values+/−SEM. (B) Luciferase activity (photons/s), measured in vivoon Day 19 (whole body imaging at necropsy): test compound is Compound258, administered at 1, 3 and 6 mg/kg, displayed versus thecorresponding vehicle control group. Data are displayed as individualdata points together with their corresponding median values andinterquartile ranges. P-values were calculated compared to thecorresponding vehicle control group and between the 3 mg/kg and 6 mg/kggroups, using the Mann Whitney test and the unpaired t-test (inparentheses) as well as the one-way ANOVA with Dunnett's post test.*=p<0.05; **=p<0.01; ***=p<0.001.

FIG. 14 is a graph showing the mean animal weight (g) profile in aMOLM13-Luc mouse model for acute myeloid leukemia tumor spread. The testcompound is Compound 258, administered at 1, 3 and 6 mg/kg, displayedversus the corresponding vehicle control group. Data are displayed asmean values+/−SEM.

FIG. 15 is a graph showing the ex vivo, post-necropsy organ/tissueluciferase activity (Photons/s/mg weight or Photon/s for lymph nodes) ina MOLM13-Luc mouse model for acute myeloid leukemia tumor spread. Testcompound is Compound 258, administered at 1, 3 and 6 mg/kg is displayedversus the corresponding Vehicle Control Group, for femur, lumbar spine,peritoneal carcinomatosis (fat tissue) and lymph nodes (both axillaryand inguinal). Data are displayed as means+/−SD. P values werecalculated compared to the corresponding Vehicle Control Group using theMann Whitney test.

FIG. 16 is a graph showing the tumor volume development in apatient-derived HPV-positive human head-and-neck squamous cell carcinomaxenograft mouse model for Compound 248 and Compound 282 (both 30 mg/kg,twice a day, administered orally).

FIG. 17 is a graph showing mice body weight development in apatient-derived HPV-positive human head-and-neck squamous cell carcinomaxenograft mouse model for Compound 248 and Compound 282 (both 30 mg/kg,twice a day, administered orally).

FIG. 18 is a graph showing the tumor volume development in apatient-derived HPV-positive human head-and-neck squamous cell carcinomaxenograft mouse model for Compound 57, Compound 248, Compound 282 andCompound 273, at variable dosages (TABLE 23). All sixteen mice treatedwith Compound 248 and Compound 273 were tumor-free at the end of theobservation period.

FIG. 19 is a graph showing mice body weight development in apatient-derived HPV-positive human head-and-neck squamous cell carcinomaxenograft mouse model for Compound 57, Compound 248, Compound 282 andCompound 273, at variable dosages (TABLE 23).

FIG. 20 is a graph showing the tumor volume development in acell-derived syngeneic mouse model for colorectal carcinoma (CT-26cells) combined with an immuno-oncology treatment (anti-PD1 antibodies).Compound 258 was administered as single agent and as a combination. Dataafter day 21 are mean+/−SEM of mice still in the experiment. Only thecombination therapies and anti-PD1 have data after day 28 (TABLE 26).Two mice displayed complete regression in the combination groups, hencethe huge SEM-values.

FIG. 21 is a graph showing mice body weight development in acell-derived syngeneic mouse model for colorectal carcinoma (CT-26cells) combined with an immuno-oncology treatment (anti-PD1 antibodies).Compound 258 was administered as single agent and as a combination. Dataafter day 21 are mean+/−SEM of mice still in the experiment. Only thecombination therapies and anti-PD1 have data after day 28 (TABLE 26).

FIG. 22 is a graph showing gene expression inhibition of threewell-characterized androgen receptor (AR)-targets through Compound258-mediated disruption of p300-CH1/TAZ1-AR signaling in thecastration-resistant prostate cancer cell line LNCaP. Prostate-specificantigen (PSA/KLK3); transmembrane serine protease 2 (TMPRSS2); andprostein (SLC45A3) gene expression was measured in 4-hourdihydrotestosterone-stimulated cells (DHT, 100 nM) and compared tountreated cells. 300 nM Compound 258 was added concomitantly to DHT.Treatment with Compound 258 resulted in complete repression of PSAstimulation, and 85%, respectively 80% repression of TMPRSS2 and SLC45A3stimulation.

FIG. 23 is a graph showing serum prostate-specific antigen (PSA) levelsin a castration resistant prostate cancer (CRPC) patient-derivedxenograft mouse model. Serum levels were determined in five mice thatstill had detectable tumors at experiment termination (following a 19day treatment period, blood samples taken 3 h after the last dose wasapplied, FIG. 3, numbering on the x-axis of FIG. 23). Two mice weretreated daily with 10 and 3 mg/kg and three mice daily with 6 mg/kgCompound 258 (FIG. 3). Minimal relative expected PSA-levels werecalculated based on minimal PSA/tumor size ratio of vehicle-treatedmice. All five mice had a clear reduction of the expected serum PSAlevels.

FIG. 24 is a graph showing tumor Vascular Endothelial Growth Factor A(VEGF) protein levels in HCT-116 and MKN45 colorectal/gastric cancercell-derived xenograft mouse model after approximately 4 and 3 weeks,respectively, of treatment with 3 mg/kg or 6 mg/kg Compound 258 (FIGS. 7and 9). In accordance with the proposed mode of action of Compound 258,the p300/CBP-HIF1alpha transcriptional complex was disturbed, resultingin VEGF protein levels which were significantly reduced upon Compound258-treatment. The effect is more evident in the HCT-116 than in theMKN45 xenograft, reflecting the higher VEGF-dependence of HCT-116xenograft vascularization (described in Dang et al. Cancer Res 2008;68(6): 1872-80).

FIG. 25 is a pair of Western blots of Compound 258-treatedHPV16-positive cervical cancer CaSki cells. The figure depicts acharacteristic rescue of p53 protein expression and p53 lysine 382acetylation (K382Ac-p53) after Compound 258-mediated inhibition ofp300/CBP-HPVE6-p53 protein-protein-interactions. Cells were treated withthe indicated concentrations (nM) for 72 h. Induction of p53 proteinabove baseline is evident at 7 nM already, acetylation of p53 lysine 382is detectable at 20 nM. Equivalent amounts of protein were loaded on theblot and the loading quantity assessed by total protein detection of thesame blot on a Bio-Rad ChemiDoc Touch imager.

DETAILED DESCRIPTION

The present invention is directed to a series of compounds having strongactivities against a broad variety of tumor types, including, but notlimited to, prostate, colon, head-and-neck and cervical cancer as wellas hematological malignancies.

The present invention is directed to a series of compounds having astrong activity as p300/CBP inhibitors, including stereoisomers,tautomers, pharmaceutically acceptable salts and prodrugs thereof, andthe use of such compounds to treat p300/CBP-related conditions ordiseases, such as cancer.

Exemplary conditions which can be treated with the disclosed compoundsinclude cancer. The cancer types which can be treated include, but arenot limited to, prostate cancer, renal cancer, pancreatic cancer, livercancer, breast cancer, gastric cancer, colorectal cancer, cervicalcancer, ovarian cancer, head-and-neck cancer, esophageal cancer,leukemia, lymphoma, lung cancer, brain cancer, cancer of the centralnervous system and skin cancer.

The invention provides pharmaceutical compositions of the describedcompounds, comprising the described compounds and pharmaceuticallyacceptable carriers, diluents or excipients.

The invention provides pharmaceutical compositions of the describedcompounds, wherein the compounds are administered in combination withone or more anti-cancer treatments or anti-cancer therapeutic agents. Inone aspect, the pharmaceutical composition consists of the combinationof one of the compounds with an immune checkpoint inhibitor ofprogrammed cell death protein 1 (PD-1).

Definitions

The following are definitions of terms used in present application. Theinitial definition provided for a group or term herein applies to thatgroup or term throughout the description and the claims, individually oras part of another group, unless otherwise indicated.

The term “alkyl” as used herein refers to a saturated straight orbranched chain group of carbon atoms derived from an alkane by theremoval of one hydrogen atom. C₁₋₃ alkyl includes, but is not limitedto, for example methyl, ethyl, n-propyl, i-propyl. C₁₋₄ alkyl comprisesfor example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,tert-butyl. C₁₋₅ alkyl comprises for example methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, C₁₋₇ alkyl comprisesfor example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,tert-butyl, n-pentyl, n-hexyl or n-heptyl. The alkyl groups of thisinvention can be optionally substituted.

The term “C₂₋₅ alkenyl” and “C₂₋₇ alkenyl” as used herein refers tostraight or branched chain hydrocarbon groups having 2 to 5 carbon atomsand 2 to 7 carbon atoms, respectively and at least one double bond.

The term “C₂₋₅ alkynyl” and “C₂₋₇ alkynyl” as used herein refers tostraight or branched chain hydrocarbon groups having 2 to 5 carbon atomsand 2 to 7 carbon atoms, respectively and at least one triple bond.

The term “C₃₋₇ cycloalkyl” and “C₃₋₅ cycloalkyl” as used herein refersto a monovalent saturated cyclic or bicyclic hydrocarbon group of 3-7 or3-5 carbons, respectively derived from a cycloalkane by the removal of asingle hydrogen atom. “C₃₋₅ cycloalkyl” includes, but is not limited to,cyclopropyl, cyclobutyl, and cyclopentyl. “C₃₋₇ cycloalkyl” includes,but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyland cycloheptyl. The term “C₃₋₇ cycloalkyl” and “C₃-s cycloalkyl” asused herein also includes cycloalkyl groups that comprise a C₁₋₃-alkylradical. Examples of such “C₃₋₇ cycloalkyl” groups comprisecyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl,2-cyclobutylethyl, cyclopentylmethyl, 2-cyclopentylethyl. Examples ofsuch “C₃₋₅ cycloalkyl” groups comprise cyclopropylmethyl,2-cyclopropylethyl, cyclobutylmethyl. Cycloalkyl groups of thisinvention can be optionally substituted. Substitutents can be e.g.halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl.

The term “C₄₋₇ cycloalkenyl” as used herein refers to a monovalentcyclic or bicyclic hydrocarbon group of 4-7 carbons having at least onedouble bond, derived from a cycloalkene by the removal of a singlehydrogen atom. The term “C₄₋₇ cycloalkenyl” as used herein also includescycloalkenyl groups that comprise a C₁₋₃-alkyl radical.

The term “C₁₋₃ alkanediyl”, “C₁₋₆ alkanediyl” and “C₁₋₇ alkanediyl” asused herein refers to a diradical of a saturated straight or branchedchain hydrocarbon group, having 1 to 3, 1 to 6 carbon and 1 to 7 carbonatoms, respectively. Examples of alkanediyl groups include methane-diyl,ethane-1,2-diyl, and the like.

The term “C₂₋₆ alkenediyl” and “C₂₋₇ alkenediyl” as used herein refersto a diradical of a straight or branched chain hydrocarbon groups having2 to 6 carbon atoms and 2 to 7 carbon atoms, respectively and at leastone double bond. Examples of alkenediyl groups include ethene-1,2-diyland the like.

The term “C₂₋₆ alkynediyl” and “C₂₋₇ alkynediyl” as used herein refersto a diradical of a straight or branched chain hydrocarbon groups having2 to 6 carbon atoms and 2 to 7 carbon atoms, respectively and at leastone triple bond. Examples of alkynediyl groups include ethene-1,2-diyland the like.

The term “C₃₋₆ cycloalkanediyl” as used herein refers to a diradicalsaturated cyclic or bicyclic hydrocarbon group of 3-6 carbons.

The term “C₃₋₆ cycloalkenediyl” as used herein refers to a diradicalcyclic or bicyclic hydrocarbon group of 3-6 carbons having at least onedouble bond.

The term “heteroalkyl” or “heteroalkanediyl” as used herein refers to analkyl radical or an alkanediyl radical as defined herein wherein one,two, three or four hydrogen atoms have been replaced with a substituentindependently selected from the group consisting of OH, NH2 and halogen.Representative examples include, but are not limited to, 2-hydroxyethyl,2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl,2-hydroxy-1-methylethyl, 2,3-dihydroxypropyl, 1-hydroxymethylethyl,3-hydroxybutyl, 2,3-dihydroxybutyl, 1-hydroxy-2-methylpropyl,3-hydroxy-1-(2-hydroxyethyl)-propyl, 2-hydroxy-1-methylpropyl,1,1,1-trifluoroethyl, 2,2,3,3-tetrafluoropropyl.

The term “aryl” as used herein refers to a mono- or bicyclic carbocyclicring system having one or two aromatic rings. The aryl group can also befused to a cyclohexane, cyclohexene, cyclopentane, or cyclopentene ringor to a cyclohexane, cyclohexene, cyclopentane, or cyclopentene ringcomprising a carbonyl group. Thus the aryl group includes e.g. indane ormono-oxo substituted indane rings. The aryl groups of this invention canbe optionally substituted as further described below. A preferred arylgroup and optionally substituted aryl group, respectively of thisinvention is a phenyl group or substituted phenyl group. Substitutentscan be e.g. halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl.

The term “heteroaryl” as used herein refers to substituted andunsubstituted aromatic 5-, or 6-membered monocyclic groups and 9- or10-membered bicyclic groups, which have at least one heteroatom (O, S orN) in at least one of the rings. Each ring of the heteroaryl groupcontaining a heteroatom can contain one or two oxygen or sulfur atomsand/or from one to four nitrogen atoms provided that the total number ofheteroatoms in each ring is four or less and each ring has at least onecarbon atom. Heteroaryl groups must include at least one fully aromaticring but the other fused ring or rings may be aromatic or non-aromatic.The heteroaryl group may be attached at any available nitrogen or carbonatom of any ring. Heteroaryl groups of this invention can be optionallysubstituted as further described below. Usually, a heteroaryl group andoptionally substituted heteroaryl group, respectively of this inventionis selected from the group consisting of substituted and/orunsubstituted aromatic 5-, or 6-membered monocyclic groups, which haveat least one heteroatom (O, S or N), preferably one heteroatom (O, S orN), more preferably one O or N in the ring, even more preferably two Nin the ring. A preferred heteroaryl group and optionally substitutedheteroaryl group, respectively of this invention is selected from thegroup consisting of a pyridinyl group, a substituted pyridinyl group, aimidazole group, a substituted imidazole group, a pyrazole group, asubstituted pyrazole group, a triazole group, a substituted triazolegroup, a benzimidazole group and a substituted benzimidazole group. Morepreferably a substituted pyridinyl group, a pyridinyl group, a triazolegroup, a substituted triazole group, a imidazole group, and/or asubstituted imidazole group, is used as heteroaryl group in the presentinvention.

Most preferably a substituted pyridinyl group, a pyridinyl group, animidazole group, and/or a substituted imidazole group, is used asheteroaryl group in the present invention. Substitutents can be e.g.halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl.

The term “S-aryl” as used herein refers to a radical —SR where R is anaryl as defined herein.

The term “O-aryl” as used herein refers to a radical —OR where R is anaryl as defined herein.

The term “S-heteroaryl” as used herein refers to a radical —SR where Ris an heteroaryl as defined herein.

The term “O-heteroaryl” as used herein refers to a radical —OR where Ris an heteroaryl as defined herein.

The term “C₁₋₃ alkyl-aryl” as used herein refers to a radical of C₁₋₃alkyl as defined herein to which an aryl group as defined herein isbonded at any carbon of the alkyl.

The term “C₁₋₃ alkyl-heteroaryl” as used herein refers to a radical ofC₁₋₃ alkyl as defined herein to which a heteroaryl group as definedherein is bonded at any carbon of the alkyl.

The terms “halo” or “halogen” as used herein refers to F, Cl, Br, or Iand is preferably F, Cl, or Br.

Compounds of the Present Disclosure

In some aspects, the present disclosure relates to a compound of Formula(Ia):

or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein:

R¹ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R² is selected from H, C(O)R¹⁴, C(O)NR¹⁵R¹⁵, C(O)OR¹⁵, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₅alkyl-OR⁸, C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₅alkyl-NHCOR¹³, or C₁₋₃ alkyl substituted by aryl or heteroaryl, whereinthe aryl or the heteroaryl is optionally substituted by halogen, C₁₋₄alkyl or C₃₋₅ cycloalkyl; with the proviso that when R² is C(O)NR¹⁵R¹⁵,both R¹⁵ can form a ring wherein the ring contains the N of NR¹⁵R¹⁵ andoptionally one further heteroatom selected from O and N, wherein if theone further heteroatom is N, it is optionally substituted by R⁸;

R³ and R⁷ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl, alloptionally substituted by halogen, OR⁸, NR⁸R¹¹, or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁴ is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁵ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, C₁₋₃ alkyl-OR⁸, or SR⁸; and whereinR⁵ can form a ring with any part of X or Y, wherein the ring optionallycontains a carbonyl group;

R⁶ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloakenyl, all optionally substituted by halogen,OR⁸, NR⁸R¹¹; C₁₋₃ alkyl substituted by C(O)NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; andwherein R⁶ can form a ring with any part of X; or is imidazolidinone;

R⁸ and R¹¹ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl;

X is selected from a bond, C₁₋₇ alkanediyl, C₂₋₇ alkenediyl, C₂₋₇alkynediyl, C₃₋₉ cycloalkanediyl, C₄₋₆ cycloalkenediyl, —O—, C₁₋₃alkanediyl-O—, —O—C₁₋₇ alkanediyl, —O—C₃₋₉ cycloalkanediyl, C₁₋₃alkanediyl-O—C₁₋₇ alkanediyl, C₁₋₇ heteroalkanediyl, or —S—C₁₋₇alkanediyl; and wherein X can form a ring or a polycyclic system withany part of R⁵, R⁶, or Y, wherein the ring optionally contains acarbonyl group;

Y is selected from H, C(O)NR¹⁰R¹², C(O)OR¹⁰, R¹⁰NC(O)NR¹⁰R¹², OC(O)R¹⁰,OC(O)NR¹⁰R¹², S(O)_(n)R⁸ wherein n is 0, 1 or 2, SO₂NR¹⁰R¹², NR¹⁰SO₂R¹⁰,NR¹⁰R¹², HNCOR⁸, CN, C₃₋₇-cycloalkyl optionally containing a heteroatomin the ring selected from O and N wherein if the heteroatom is N it isoptionally substituted by R⁸; S-aryl, O-aryl, S-heteroaryl, O-heteroarylwherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionallysubstituted by one or more R⁹ or R¹⁴; or aryl, heteroaryl wherein thearyl or heteroaryl is optionally substituted by one or more of R⁸; andwherein Y can form a ring with any part of X or R⁵, wherein the ringoptionally contains a carbonyl group; with the proviso that when Y isC(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² can form a ring optionallysubstituted by R⁹ or R¹⁴; wherein the ring contains the N of NR¹⁰R¹² andoptionally one further heteroatom selected from O and N, wherein if theone further heteroatom is N, it is optionally substituted by R⁸;

R⁹ is selected from H, halogen, C₁₋₅ alkyl, C₂₋₅ alkenyl, C₂₋₅ alkynyl,C₃₋₅ cycloalkyl, C₁₋₅ alkyl-OR⁸, C₁₋₅ alkyl-SR⁸, C₁₋₅ alkyl-NR⁸R¹¹, C₁₋₅alkyl-C(O)OR⁸, C₁₋₅ alkyl-C(O)NR⁸R¹¹, C₁₋₅ alkyl-C(O)R¹⁰, CN, C(O)R⁸,C(O)NR⁸R¹¹, C(O)OR⁸, NR⁸C(O)NR⁸R¹¹, OC(O)NR⁸R¹¹, SO₂NR⁸R¹¹, NR⁸SO₂R⁸,OR⁸, NR⁸R¹¹, or S(O)_(n)R⁸ wherein n is 0, 1 or 2;

R¹⁰ and R¹² are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₃alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₃ alkyl-aryl, C₁₋₃alkyl-heteroaryl, all these groups optionally substituted by halogen,OR⁸, or NR⁸R¹¹;

R¹³ is C₁₋₅ alkyl substituted by a bicyclic ring optionally containingat least one heteroatom and a carbonyl group;

R¹⁴ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; and

each R¹⁵ is independently selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, or C₁₋₃alkyl-OR⁸.

In some aspects, the present disclosure relates to a compound of Formula(I):

or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein:

R¹ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R² is selected from H, C(O)R¹⁴, C(O)NR¹⁵R¹⁵, C(O)OR¹⁵, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₅alkyl-OR⁸, C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₅alkyl-NHCOR¹³, or C₁₋₃ alkyl substituted by aryl or heteroaryl, whereinthe aryl or the heteroaryl is optionally substituted by halogen, C₁₋₄alkyl or C₃₋₅ cycloalkyl; with the proviso that when R² is C(O)NR¹⁵R¹⁵,both R¹⁵ can form a ring wherein the ring contains the N of NR¹⁵R¹⁵ andoptionally one further heteroatom selected from O and N, wherein if theone further heteroatom is N, it is optionally substituted by R⁸;

R³ and R⁷ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl, alloptionally substituted by halogen, OR⁸, NR⁸R¹¹, or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁴ is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁵ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, C₁₋₃ alkyl-OR⁸, or SR⁸; and whereinR⁵ can form a ring with any part of X or Y, wherein the ring optionallycontains a carbonyl group;

R⁶ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloakenyl, all optionally substituted by halogen,OR⁸, NR⁸R¹¹; C₁₋₃ alkyl substituted by C(O)NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; or isimidazolidinone;

R⁸ and R¹¹ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl;

X is selected from a bond, C₁₋₇ alkanediyl, C₂₋₇ alkenediyl, C₂₋₇alkynediyl, C₃₋₆ cycloalkanediyl, C₄₋₆ cycloalkenediyl, —O—, C₁₋₃alkanediyl-O—, —O—C₁₋₇ alkanediyl, C₁₋₃ alkanediyl-O—C₁₋₇ alkanediyl,C₁₋₇ heteroalkanediyl, or —S—C₁₋₇ alkanediyl; and wherein X can form aring with any part of R⁵ or Y, wherein the ring optionally contains acarbonyl group;

Y is selected from H, C(O)NR¹⁰R¹², C(O)OR¹⁰, R¹⁰NC(O)NR¹⁰R¹², OC(O)R¹⁰,OC(O)NR¹⁰R¹², S(O)_(n)R⁸ wherein n is 0, 1 or 2, SO₂NR¹⁰R¹², NR⁰SO₂R⁰,NR¹⁰R¹², HNCOR⁸, CN, C₃₋₇-cycloalkyl optionally containing a heteroatomin the ring selected from O and N wherein if the heteroatom is N it isoptionally substituted by R⁸; S-aryl, O-aryl, S-heteroaryl, O-heteroarylwherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionallysubstituted by one or more R⁹ or R¹⁴; or aryl, heteroaryl wherein thearyl or heteroaryl is optionally substituted by one or more of R⁸; andwherein Y can form a ring with any part of X or R⁵, wherein the ringoptionally contains a carbonyl group; with the proviso that when Y isC(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² can form a ring wherein the ringcontains the N of NR¹⁰R¹² and optionally one further heteroatom selectedfrom O and N, wherein if the one further heteroatom is N, it isoptionally substituted by R⁸;

R⁹ is selected from H, halogen, C₁₋₅ alkyl, C₂₋₅ alkenyl, C₂₋₅ alkynyl,C₃₋₅ cycloalkyl, C₁₋₅ alkyl-OR⁸, C₁₋₅ alkyl-SR⁸, C₁₋₅ alkyl-NR⁸R¹¹, C₁₋₅alkyl-C(O)OR⁸, C₁₋₅ alkyl-C(O)NR⁸R¹¹, C₁₋₅ alkyl-C(O)R¹⁰, CN, C(O)R⁸,C(O)NR⁸R¹¹, C(O)OR⁸, NR⁸C(O)NR⁸R¹¹, OC(O)NR⁸R¹¹, SO₂NR⁸R¹¹, NR⁸SO₂R⁸,OR⁸, NR⁸R¹¹, or S(O)_(n)R⁸ wherein n is 0, 1 or 2;

R¹⁰ and R¹² are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₃alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₃ alkyl-aryl, or C₁₋₃alkyl-heteroaryl, all these groups optionally substituted by halogen,OR⁸, or NR⁸R¹¹;

R¹³ is C₁₋₅ alkyl substituted by a bicyclic ring optionally containingat least one heteroatom and a carbonyl group;

R¹⁴ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; and

each R¹⁵ is independently selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, or C₁₋₃alkyl-OR⁸.

It is understood that, for a compound of Formula (I) or Formula (Ia),R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, X, andY can each be, where applicable, selected from the groups describedherein, and any group described herein for any of R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, X, and Y can be combined,where applicable, with any group described herein for one or more of theremainder of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³,R¹⁴, R¹⁵, X, and Y.

In some embodiments, R¹ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkylsubstituted by cycloalkyl, aryl or heteroaryl, wherein the cycloalkyl,aryl or the heteroaryl is optionally substituted by halogen, C₁₋₄ alkylor C₃₋₅ cycloalkyl

In some embodiments, R¹ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl.

In some embodiments, R¹ is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substitutedby aryl or heteroaryl, wherein the aryl or the heteroaryl is optionallysubstituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl.

In some embodiments, R¹ is selected from C₂₋₇ alkyl, C₃₋₇ cycloalkyl, orC₁₋₃ alkyl substituted by aryl or heteroaryl, wherein the aryl or theheteroaryl is optionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅cycloalkyl.

In some embodiments, R¹ is selected from C₃₋₇ alkyl, C₃₋₇ cycloalkyl, orC₁₋₃ alkyl substituted by aryl or heteroaryl.

In some embodiments, R¹ is H.

In some embodiments, R¹ is C₃₋₇ cycloalkyl.

In some embodiments, R¹ is selected from cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl.

In some embodiments, R¹ is selected from cyclopropyl or cyclohexyl.

In some embodiments, R¹ is cyclopropyl.

In some embodiments, R¹ is cyclohexyl.

In some embodiments, R¹ is C₁₋₇ alkyl.

In some embodiments, R¹ is C₂₋₇ alkyl.

In some embodiments, R¹ is C₃₋₇ alkyl.

In some embodiments, R¹ is selected from methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl.

In some embodiments, R¹ is selected from ethyl, propyl, isopropyl,butyl, sec-butyl, isobutyl, or tert-butyl.

In some embodiments, R¹ is selected from propyl, isopropyl, butyl,sec-butyl, isobutyl, or tert-butyl.

In some embodiments, R¹ is isobutyl.

In some embodiments, R¹ is C₁₋₃ alkyl substituted by cycloalkyl.

In some embodiments, R¹ is methyl, ethyl, or propyl substituted bycyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

In some embodiments, R¹ is ethyl or propyl substituted by cyclopropyl orcyclohexyl.

In some embodiments, R¹ is C₁₋₃ alkyl substituted by aryl or heteroaryl.

In some embodiments, R¹ is methyl, ethyl, or propyl substituted byphenyl, imidazole, pyridine, or triazole.

In some embodiments, R¹ is ethyl or propyl substituted by phenyl orpyridine.

In some embodiments, R¹ is ethyl substituted by phenyl.

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R² is selected from H, C(O)R¹⁴, C(O)NR¹⁵R¹⁵,C(O)OR¹⁵, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, C₁₋₅ alkyl-OR⁸, C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃alkanediyl, C₁₋₅ alkyl-NHCOR¹³, or C₁₋₃ alkyl substituted by cycloalkyl,aryl or heteroaryl, wherein the cycloalkyl, aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; withthe proviso that when R² is C(O)NR¹⁵R¹⁵, both R¹⁵ can form a ringwherein the ring contains the N of NR¹⁵R¹⁵ and optionally one furtherheteroatom selected from O and N, wherein if the one further heteroatomis N, it is optionally substituted by R⁸;

In some embodiments, R² is selected from H, C(O)R¹⁴, C(O)NR⁵R¹⁵,C(O)OR¹⁵, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, C₁₋₅ alkyl-OR⁸, C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃alkanediyl, C₁₋₅ alkyl-NHCOR¹³, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; with the proviso that when R²is C(O)NR¹⁵R¹⁵, both R¹⁵ can form a ring wherein the ring contains the Nof NR¹⁵R¹⁵ and optionally one further heteroatom selected from O and N,wherein if the one further heteroatom is N, it is optionally substitutedby R⁸;

In some embodiments, R² is selected from H, C(O)R¹⁴, C(O)OR¹⁵, C₁₋₇alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃alkanediyl, C₁₋₅ alkyl-OR⁸, C₁₋₅ alkyl-NHCOR¹³, or C₁₋₃ alkylsubstituted by aryl, wherein the aryl is optionally substituted byhalogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl.

In some embodiments, R² is selected from H, C(O)R¹⁴, C₁₋₇ alkyl, C₃₋₇cycloalkyl, C₁₋₅ alkyl-OR⁸, C₁₋₅ alkyl-NHCOR¹³, or C₁₋₃ alkylsubstituted by aryl, wherein the aryl is optionally substituted byhalogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl.

In some embodiments, R² is selected from H, C(O)R¹⁴, wherein R¹⁴ is C₁₋₇alkyl; C₁₋₇ alkyl, C₃₋₇ cycloalkyl, C₁₋₅ alkyl-OR; C₁₋₅ alkyl-NHCOR¹³,wherein R¹³ ispentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3-one; orC₁₋₃ alkyl substituted by aryl, wherein the aryl is optionallysubstituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl.

In some embodiments, R² is selected from H, C(O)R¹⁴, wherein R¹⁴ is C₁₋₇alkyl; C₁₋₇ alkyl, C₃₋₇ cycloalkyl, C₁₋₅ alkyl-OR⁸, wherein R⁸ is C₁₋₇alkyl; C₁₋₅ alkyl-NHCOR¹³, wherein R¹³ ispentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3-one; orC₁₋₃ alkyl substituted by aryl, wherein the aryl is optionallysubstituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl.

In some embodiments, R² is H.

In some embodiments, R² is C₁₋₇ alkyl.

In some embodiments, R² is selected from methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl.

In some embodiments, R² is selected from methyl, ethyl, or propyl.

In some embodiments, R² is C(O)R¹⁴, and R¹⁴ is methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl.

In some embodiments, R² is C(O)NR¹⁵R¹⁵, wherein each R¹⁵ isindependently selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl,C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, or C₁₋₃ alkyl-OR⁸.

In some embodiments, R² is C(O)NR¹⁵R¹⁵, wherein each R¹⁵ isindependently selected from methyl, ethyl, propyl, isopropyl, butyl,sec-butyl, isobutyl, or tert-butyl.

In some embodiments, R² is C(O)NR¹⁵R¹⁵, wherein each R¹⁵ isindependently selected from methyl or ethyl.

In some embodiments, R² is C(O)NR¹⁵R¹⁵, wherein each R¹⁵ is methyl.

In some embodiments, R² is C₃₋₇ cycloalkyl.

In some embodiments, R² is selected from cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl.

In some embodiments, R² is cyclopropyl.

In some embodiments, R² is C₁₋₅ alkyl-OR⁸, wherein R⁸ is C₁₋₇ alkyl

In some embodiments, R² is methyl-OR⁸, ethyl-OR⁸, propyl-OR⁸, orbutyl-OR⁸ wherein R⁸ is methyl, ethyl, propyl, or butyl.

In some embodiments, R² is ethyl-OR⁸ wherein R⁸ is methyl, ethyl,propyl, or butyl.

In some embodiments, R² is ethyl-OR⁸ wherein R⁸ is methyl.

In some embodiments, R² is C₁₋₃ alkyl substituted by cycloalkyl.

In some embodiments, R² is methyl, ethyl, or propyl substituted bycyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

In some embodiments, R² is ethyl or propyl substituted by cyclopropyl orcyclohexyl.

In some embodiments, R² is ethyl substituted by cyclopropyl.

In some embodiments, R² is C₁₋₃ alkyl substituted by aryl or heteroaryl.

In some embodiments, R² is methyl, ethyl, or propyl substituted byphenyl, imidazole, pyridine, or triazole.

In some embodiments, R² is ethyl or propyl substituted by phenyl orpyridine.

In some embodiments, R² is ethyl substituted by phenyl.

In some embodiments, R² is C₁₋₃ alkyl substituted by aryl or heteroaryl,wherein the aryl or heteroaryl is optionally substituted by halogen,C₁₋₄ alkyl or C₃₋₅ cycloalkyl.

In some embodiments, R² is methyl, ethyl, or propyl substituted byphenyl, imidazole, pyridine, or triazole substituted by fluoro, iodo, orbromo.

In some embodiments, R² is ethyl or propyl substituted by phenyl orpyridine substituted fluoro, iodo, or bromo.

In some embodiments, R² is ethyl substituted by phenyl substitutedfluoro.

In some embodiments, R² is

In some embodiments, R² is C₁₋₅ alkyl-NHCOR¹³, wherein R¹³ ispentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3-one.

In some embodiments, R² is methyl-NHCOR¹³, ethyl-NHCOR¹³,propyl-NHCOR¹³, butyl-NHCOR¹³, or pentyl-NHCOR¹³, wherein R¹³ ispentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3-one.

In some embodiments, R² is pentyl-NHCOR¹³, wherein R¹³ ispentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3-one.

In some embodiments, R² is

In some embodiments, R² is C₁₋₃ alkyl substituted by aryl, wherein thearyl is optionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅cycloalkyl.

In some embodiments, R² is

In some embodiments, R³ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl, all optionallysubstituted by halogen, OR⁸, NR⁸R¹¹, or C₁₋₃ alkyl substituted by arylor heteroaryl, wherein the aryl or the heteroaryl is optionallysubstituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl.

In some embodiments, R³ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl.

In some embodiments, R³ is C₁₋₇ alkyl.

In some embodiments, R³ is selected from methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl.

In some embodiments, R³ is C₂₋₇ alkenyl.

In some embodiments, R³ is vinyl.

In some embodiments, R³ is C₃₋₇ cycloalkyl.

In some embodiments, R³ is selected from cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl.

In some embodiments, R³ is H.

In some embodiments, R³ and R⁷ are each independently selected from H,C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇cycloalkenyl, all optionally substituted by halogen, OR⁸, NR⁸R¹¹, orC₁₋₃ alkyl substituted by aryl or heteroaryl, wherein the aryl or theheteroaryl is optionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅cycloalkyl

In some embodiments, R³ and R⁷ are each independently selected from H,C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇cycloalkenyl.

In some embodiments, R³ and R⁷ are each independently C₁₋₇ alkyl.

In some embodiments, R³ and R⁷ are each independently selected frommethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, ortert-butyl.

In some embodiments, R³ and R⁷ are each independently C₂₋₇ alkenyl.

In some embodiments, R³ and R⁷ are each vinyl.

In some embodiments, R³ and R⁷ are each independently C₃₋₇ cycloalkyl.

In some embodiments, R³ and R⁷ are each independently selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

In some embodiments, R³ and R⁷ are each H.

In some embodiments, R⁷ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl, all optionallysubstituted by halogen, OR⁸, NR⁸R¹¹, or C₁₋₃ alkyl substituted by arylor heteroaryl, wherein the aryl or the heteroaryl is optionallysubstituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl.

In some embodiments, R⁷ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl.

In some embodiments, R⁷ is C₁₋₇ alkyl.

In some embodiments, R⁷ is selected from methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl.

In some embodiments, R⁷ is C₂₋₇ alkenyl.

In some embodiments, R⁷ is vinyl.

In some embodiments, R⁷ is C₃₋₇ cycloalkyl.

In some embodiments, R⁷ is selected from cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl.

In some embodiments, R⁷ is H.

In some embodiments, the group R⁷ is in position −5 of the piperidinering.

In some embodiments, the group R⁷ is in position −6 of the piperidinering.

In some embodiments, the group R⁶ is in position −2 of the piperidinering.

In some embodiments, the group R⁶ is in position −2 of the piperidinering and/or the group R⁷ is in position −5 of the piperidine ring.

In some embodiments, the group R⁶ is in position −2 of the piperidinering and the group R⁷ is in position −5 of the piperidine ring.

In some embodiments, R⁴ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkylsubstituted by cycloalkyl, aryl or heteroaryl, wherein the cycloalkyl,aryl or the heteroaryl is optionally substituted by halogen, C₁₋₄ alkylor C₃₋₅ cycloalkyl

In some embodiments, R⁴ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl.

In some embodiments, R⁴ is selected from C₁₋₇ alkyl, C₃₋₇ cycloalkyl, orC₁₋₃ alkyl substituted by aryl or heteroaryl, wherein the aryl or theheteroaryl is optionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅cycloalkyl.

In some embodiments, R⁴ is selected from C₂₋₇ alkyl, C₃₋₇ cycloalkyl, orC₁₋₃ alkyl substituted by aryl or heteroaryl, wherein the aryl or theheteroaryl is optionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅cycloalkyl.

In some embodiments, R⁴ is selected from C₃₋₇ alkyl, C₃₋₇ cycloalkyl, orC₁₋₃ alkyl substituted by aryl or heteroaryl.

In some embodiments, R⁴ is H.

In some embodiments, R⁴ is C₃₋₇ cycloalkyl.

In some embodiments, R⁴ is selected from cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl.

In some embodiments, R⁴ is selected from cyclopropyl or cyclohexyl.

In some embodiments, R⁴ is cyclopropyl.

In some embodiments, R⁴ is cyclohexyl.

In some embodiments, R⁴ is C₁₋₇ alkyl.

In some embodiments, R⁴ is C₂₋₇ alkyl.

In some embodiments, R⁴ is C₃₋₇ alkyl.

In some embodiments, R⁴ is selected from methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl.

In some embodiments, R⁴ is selected from ethyl, propyl, isopropyl,butyl, sec-butyl, isobutyl, or tert-butyl.

In some embodiments, R⁴ is selected from propyl, isopropyl, butyl,sec-butyl, isobutyl, or tert-butyl.

In some embodiments, R⁴ is isobutyl.

In some embodiments, R⁴ is C₁₋₃ alkyl substituted by cycloalkyl.

In some embodiments, R⁴ is methyl, ethyl, or propyl substituted bycyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

In some embodiments, R⁴ is ethyl or propyl substituted by cyclopropyl orcyclohexyl.

In some embodiments, R⁴ is C₁₋₃ alkyl substituted by aryl or heteroaryl.

In some embodiments, R⁴ is methyl, ethyl, or propyl substituted byphenyl, imidazole, pyridine, or triazole.

In some embodiments, R⁴ is ethyl or propyl substituted by phenyl orpyridine.

In some embodiments, R⁴ is ethyl substituted by phenyl.

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, the compound is of any one of Formulae (IIa),(IIb), or (IIc):

or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X, and Y are as describedherein.

In some embodiments, the compound is of Formula (IIa) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X, and Y are as describedherein.

In some embodiments, the compound is of Formula (IIb) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X, and Y are as describedherein.

In some embodiments, the compound is of Formula (IIc) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X, and Y are as describedherein.

In some embodiments, the compound is of any one of Formulae (IIIa),(IIIb), (IIIc), or (IIId):

or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein R¹, R⁴, R⁵, R⁶, X, and Y are as described herein.

In some embodiments, the compound is of Formula (IIIa) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein R¹, R⁴, R⁵, R⁶, X, and Y are as described herein.

In some embodiments, the compound is of Formula (IIIb) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein R¹, R⁴, R⁵, R⁶, X, and Y are as described herein.

In some embodiments, the compound is of Formula (IIIc) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein R¹, R⁴, R⁵, R⁶, X, and Y are as described herein.

In some embodiments, the compound is of Formula (IIId) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein R¹, R⁴, R⁵, R⁶, X, and Y are as described herein.

In some embodiments, the group R⁶ is in position −2 of the piperidinering.

In some embodiments, the group R⁶ is in position −3 of the piperidinering.

In some embodiments, the group R⁶ is in position −2 of the piperidinering and/or the group R⁷ is in position −5 of the piperidine ring.

In some embodiments, the group R⁶ is in position −2 of the piperidinering and the group R⁷ is in position −5 of the piperidine ring.

In some embodiments, R⁶ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloakenyl, all optionallysubstituted by halogen, OR⁸, NR⁸R¹¹; C₁₋₃ alkyl substituted byC(O)NR⁸R¹¹; or C₁₋₃ alkyl substituted by aryl or heteroaryl, wherein thearyl or the heteroaryl is optionally substituted by halogen, C₁₋₄ alkylor C₃₋₅ cycloalkyl; and wherein R⁶ can form a ring with any part of X;or is imidazolidinone.

In some embodiments, R⁶ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloakenyl, all optionallysubstituted by halogen, OR⁸, NR⁸R¹¹; C₁₋₃ alkyl substituted byC(O)NR⁸R¹¹; or C₁₋₃ alkyl substituted by aryl or heteroaryl, wherein thearyl or the heteroaryl is optionally substituted by halogen, C₁₋₄ alkylor C₃₋₅ cycloalkyl; or is imidazolidinone.

In some embodiments, R⁶ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl; or isimidazolidinone.

In some embodiments, R⁶ is H, C₁₋₇ alkyl, or imidazolidinone.

In some embodiments, R⁶ is H or C₁₋₇ alkyl.

In some embodiments, R⁶ is H.

In some embodiments, R⁶ is in position −2 of the piperidine ring and isH.

In some embodiments, R⁶ is in position −3 of the piperidine ring and isH.

In some embodiments, R⁶ is imidazolidinone.

In some embodiments, R⁶ is

In some embodiments, R⁶ is C₁₋₇ alkyl.

In some embodiments, R⁶ is selected from methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl.

In some embodiments, R⁶ is methyl.

In some embodiments, R⁶ is in position −2 of the piperidine ring and isC₁₋₇ alkyl.

In some embodiments, R⁶ is in position −2 of the piperidine ring and isselected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,isobutyl, or tert-butyl.

In some embodiments, R⁶ is in position −2 of the piperidine ring and ismethyl.

In some embodiments, R⁶ is selected from the group consisting of H,

In some embodiments, R⁶ is in position −2 of the piperidine ring and isselected from the group consisting of H,

In some embodiments, R⁶ is

In some embodiments, R⁶ is in position −2 of the piperidine ring and is

In some embodiments, R⁶ is C₁₋₃ alkyl substituted by C(O)NR⁸R¹¹.

In some embodiments, R⁶ is C₁₋₃ alkyl substituted by C(O)NR⁸R¹¹, whereinR⁸ is H.

In some embodiments, R⁶ is C₁₋₃ alkyl substituted by C(O)NR⁸R¹¹, whereinR¹¹ is H.

In some embodiments, R⁶ is C₁₋₃ alkyl substituted by C(O)NR⁸R¹¹, whereinR⁸ and R¹¹ is H.

In some embodiments, R⁶ is C₁₋₃ alkyl substituted by C(O)NH₂.

In some embodiments, R⁶ is methyl, ethyl, or propyl substituted byC(O)NH₂.

In some embodiments, R⁶ is ethyl substituted by C(O)NH₂.

In some embodiments, R⁶ is propyl substituted by C(O)NH₂.

In some embodiments, R⁶ is selected from the group consisting of

In some embodiments, R⁶ is in position −3 of the piperidine ring and isselected from the group consisting of

In some embodiments, R⁶ forms a ring with any part of X.

In some embodiments, R⁶ is in position −3 of the piperidine ring andforms a ring with any part of X.

In some embodiments, R⁶ is in position −3 of the piperidine ring andforms a 3-membered, a 4-membered, 5-membered, or 6-membered ring withany part of X.

In some embodiments, R⁶ is in position −3 of the piperidine ring andforms a 4-membered or 6-membered ring with any part of X.

In some embodiments, R⁶ is in position −3 of the piperidine ring andforms a 4-membered or ring with any part of X.

In some embodiments, R⁶ is in position −3 of the piperidine ring andforms a 6-membered ring with any part of X.

In some embodiments, the compound is of any one of Formulae (IVa),(IVb), (IVc) or (IVd):

or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein R¹, R², R⁴, R⁵, R⁶, X, and Y are as described herein.

In some embodiments, the compound is of Formula (IVa) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein R¹, R², R⁴, R⁵, R⁶, X, and Y are as described herein.

In some embodiments, the compound is of Formula (IVb) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein R¹, R², R⁴, R⁵, R⁶, X, and Y are as described herein.

In some embodiments, the compound is of Formula (IVc) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein R¹, R², R⁴, R⁵, R⁶, X, and Y are as described herein.

In some embodiments, the compound is of Formula (IVd) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein R¹, R², R⁴, R⁵, R⁶, X, and Y are as described herein.

In some embodiments, R⁵ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, C₁₋₃ alkyl-OR⁸,or SR⁸; and wherein R⁵ can form a ring with any part of X or Y, whereinthe ring optionally contains a carbonyl group;

In some embodiments, R⁵ is selected from H, C₁₋₇ alkyl, OR⁸, or SR⁸; andwherein C₁₋₇ alkyl, OR⁸ or SR⁸ of R⁵ can form a ring with any part of Xor Y, wherein the ring optionally contains a carbonyl group.

In some embodiments, R⁵ is selected from H, C₁₋₇ alkyl, OR⁸, or SR⁸; andwherein C₁₋₇ alkyl, OR⁸ or SR⁸ of R⁵ can form a ring with any part of Xor, when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², C₁₋₇ alkyl of R⁵ can form a ringwith any part of Y, wherein the ring optionally contains a carbonylgroup.

In some embodiments, R⁵ is selected from H, C₁₋₇ alkyl, or OR⁸; andwherein C₁₋₇ alkyl or OR⁸ can form a ring with any part of X or Y,wherein the ring optionally contains a carbonyl group.

In some embodiments, R⁵ is selected from H, C₁₋₇ alkyl, or OR⁸; andwherein C₁₋₇ alkyl or OR⁸ of R⁵ can form a ring with any part of X or,when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², C₁₋₇ alkyl of R⁵ can form a ring withany part of Y, wherein the ring optionally contains a carbonyl group.

In some embodiments, R⁵ is selected from C₁₋₇ alkyl, OR⁸, or SR⁸;wherein C₁₋₇ alkyl, OR⁸ or SR⁸ can form a ring with any part of X.

In some embodiments, R⁵ is OR⁸, wherein R⁸ of OR⁸ is C₁₋₇ alkyl, andwherein OR⁸ can form a ring with any part of X.

In some embodiments, R⁵ is selected from H and C₁₋₇ alkyl; and whereinC₁₋₇ alkyl can form a ring with any part of X or Y, wherein the ringoptionally contains a carbonyl group.

In some embodiments, R⁵ is selected from H and C₁₋₇ alkyl; and whereinC₁₋₇ alkyl of R⁵ can form a ring with any part of X or, when Y is isC(O)NR¹⁰R¹² or NR¹⁰R¹², C₁₋₇ alkyl of R⁵ can form a ring with any partof Y, wherein the ring optionally contains a carbonyl group.

In some embodiments, R⁵ is selected from H and C₁₋₇ alkyl.

In some embodiments, R⁵ is selected from H, methyl, and ethyl.

In some embodiments, R⁵ is H.

In some embodiments, R⁵ is methyl.

In some embodiments, R⁵ is ethyl.

In some embodiments, R⁸ and R¹¹ are each independently selected from H,C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇cycloalkenyl.

In some embodiments, R⁸ and R¹¹ are each independently selected from H,C₁₋₇ alkyl, C₂₋₇ alkenyl, and C₃₋₇ cycloalkyl.

In some embodiments, R⁸ is C₁₋₇ alkyl and/or R¹¹ is selected from H,C₁₋₇ alkyl, C₂₋₇ alkenyl, and C₃₋₇ cycloalkyl.

In some embodiments, R⁸ is C₁₋₇ alkyl and/or R¹¹ is C₁₋₇ alkyl.

In some embodiments, R⁹ is selected from H, halogen, C₁₋₅ alkyl, C₂₋₅alkenyl, C₂₋₅ alkynyl, C₃₋₅ cycloalkyl, C₁₋₅ alkyl-OR⁸, C₁₋₅ alkyl-SR⁸,C₁₋₅ alkyl-NR⁸R¹¹, C₁₋₅ alkyl-C(O)OR⁸, C₁₋₅ alkyl-C(O)NR⁸R¹¹, C₁₋₅alkyl-C(O)R¹⁰, CN, C(O)R⁸, C(O)NR⁸R¹¹, C(O)OR⁸, NR⁸C(O)NR⁸R¹¹,OC(O)NR⁸R¹¹, SO₂NR⁸R¹¹, NR⁸SO₂R⁸, OR⁸, NR⁸R¹¹, or S(O)_(n)R⁸ wherein nis 0, 1 or 2.

In some embodiments, R⁹ is selected from H, C₁₋₅ alkyl, halogen, C₁₋₅alkyl-NR⁸R¹¹, C₁₋₅ alkyl-C(O)OR⁸, C₁₋₅ alkyl-C(O)NR⁸R¹¹, CN, C(O)R⁸,C(O)NR⁸R¹¹, C(O)OR⁸, and OR⁸.

In some embodiments, R¹⁰ and R¹² are each independently selected from H,C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₃alkyl-aryl, or C₁₋₃ alkyl-heteroaryl, all these groups optionallysubstituted by halogen, OR⁸, or NR⁸R¹¹.

In some embodiments, R¹⁰ and R¹² are each independently selected from H,C₁₋₇ alkyl, C₂₋₇ alkenyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₃alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₃ alkyl-aryl, or C₁₋₃alkyl-heteroaryl, all these groups optionally substituted by halogen orOR⁸.

In some embodiments, R¹⁰ and R¹² are each independently selected from H,C₁₋₇ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃alkanediyl, or C₁₋₃ alkyl-aryl, all these groups optionally substitutedby halogen.

In some embodiments, Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², and R¹⁰ and R¹² canform a ring optionally substituted by R⁹ or R¹⁴; wherein the ringcontains the N of NR¹⁰R¹² and optionally one further heteroatom selectedfrom O and N, wherein if the one further heteroatom is N, it isoptionally substituted by R⁸.

In some embodiments, R¹³ is C₁₋₅ alkyl substituted by a bicyclic ringoptionally containing at least one heteroatom and a carbonyl group.

In some embodiments, R¹⁴ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl.

In some embodiments, R¹⁴ is selected from C₁₋₇ alkyl, C₃₋₇ cycloalkyl,or C₁₋₃ alkyl substituted by aryl or heteroaryl, wherein the aryl or theheteroaryl is optionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅cycloalkyl.

In some embodiments, R¹⁴ is selected from C₁₋₇ alkyl and C₃₋₇cycloalkyl.

In some embodiments, R¹⁴ is C₁₋₇ alkyl.

In some embodiments, each R¹⁵ is independently selected from H, C₁₋₇alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl,OR⁸, or C₁₋₃ alkyl-OR⁸.

In some embodiments, each R¹⁵ is independently selected from H, C₁₋₇alkyl, and C₃₋₇ cycloalkyl.

In some embodiments, each R¹⁵ is independently selected from H and C₁₋₇alkyl.

In some embodiments, X is selected from a bond, C₁₋₇ alkanediyl, C₂₋₇alkenediyl, C₂₋₇ alkynediyl, C₃₋₉ cycloalkanediyl, C₄₋₆ cycloalkenediyl,—O—, C₁₋₃ alkanediyl-O—, —O—C₁₋₇ alkanediyl, —O—C₃₋₉ cycloalkanediyl,C₁₋₃ alkanediyl-O—C₁₋₇ alkanediyl, C₁₋₇ heteroalkanediyl, or —S—C₁₋₇alkanediyl; and wherein X can form a ring or a polycyclic system withany part of R⁵, R⁶, or Y, wherein the ring optionally contains acarbonyl group.

In some embodiments, X is selected from a bond, C₁₋₇ alkanediyl, C₂₋₇alkenediyl, C₂₋₇ alkynediyl, C₃₋₆ cycloalkanediyl, C₄₋₆ cycloalkenediyl,—O—, C₁₋₃ alkanediyl-O—, —O—C₁₋₇ alkanediyl, C₁₋₃ alkanediyl-O—C₁₋₇alkanediyl, C₁₋₇ heteroalkanediyl, or —S—C₁₋₇ alkanediyl; and wherein Xcan form a ring with any part of R⁵ or Y, wherein the ring optionallycontains a carbonyl group.

In some embodiments, X is selected from a bond, C₁₋₇ alkanediyl, —O—,C₁₋₃ alkanediyl-O—, —O—C₁₋₇ alkanediyl, C₁₋₃ alkanediyl-O—C₁₋₇alkanediyl, C₁₋₇ heteroalkanediyl, or —S—C₁₋₇ alkanediyl; and wherein Xcan form a ring with any part of R⁵ or Y, wherein the ring optionallycontains a carbonyl group.

In some embodiments, X is selected from a bond, C₁₋₇ alkanediyl, —O—,C₁₋₃ alkanediyl-O—, —O—C₁₋₇ alkanediyl, C₁₋₃ alkanediyl-O—C₁₋₇alkanediyl, C₁₋₇ heteroalkanediyl, or —S—C₁₋₇ alkanediyl; and wherein Xcan form a ring with any part of R⁵ or, when Y is C(O)NR¹⁰R¹² orNR¹⁰R¹², X can form a ring with any part of Y, wherein the ringoptionally contains a carbonyl group.

In some embodiments, X is selected from a bond, —O—C₁₋₇ alkanediyl,—S—C₁₋₇ alkanediyl and C₁₋₇ alkanediyl; and wherein —O—C₁₋₇ alkanediyl,S—C₁₋₇ alkanediyl or C₁₋₇ alkanediyl of X can form a ring with any partof R⁵ or Y, wherein the ring optionally contains a carbonyl group.

In some embodiments, X is selected from a bond, —O—C₁₋₇ alkanediyl andC₁₋₇ alkanediyl; and wherein —O—C₁₋₇ alkanediyl or C₁₋₇ alkanediyl of Xcan form a ring with any part of R⁵ or, when Y is C(O)NR¹⁰R¹² orNR¹⁰R¹², C₁₋₇ alkanediyl of X can form a ring with any part of Y,wherein the ring optionally contains a carbonyl group.

In some embodiments, X is selected from a bond, —O—C₁₋₇ alkanediyl,S—C₁₋₇ alkanediyl and C₁₋₇ alkanediyl, and wherein —O—C₁₋₇ alkanediyl,S—C₁₋₇ alkanediyl or C₁₋₇ alkanediyl can form a ring with any part ofR⁵, wherein the ring optionally contains a carbonyl group.

In some embodiments, X is selected from a bond and C₁₋₇ alkanediyl,wherein C₁₋₇ alkanediyl can form a ring with any part of R⁵ or Y.

In some embodiments, X is selected from a bond and C₁₋₇ alkanediyl,wherein C₁₋₇ alkanediyl of X can form a ring with any part of R⁵ or,when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², C₁₋₇ alkanediyl of X can form a ringwith any part of Y.

In some embodiments, X is selected from a bond and C₁₋₇ alkanediyl,wherein C₁₋₇ alkanediyl can form a ring with any part of Y.

In some embodiments, X is selected from a bond and C₁₋₇ alkanediyl,wherein C₁₋₇ alkanediyl of X can form a ring with any part of Y when Yis C(O)NR¹⁰R¹² or NR¹⁰R¹².

In some embodiments, the ring which can be formed by R⁵ and any part ofX or Y, the ring which can be formed by X and any part of R⁵ or Y,and/or the ring which can be formed by Y and any part of X or R⁵ is anon-aromatic ring, preferably a non-aromatic ring containing betweenfour and six atoms e.g. between four and six carbon and heteroatoms,more preferably a non-aromatic ring containing between three and fivecarbon and one nitrogen atom or a non-aromatic ring containing betweentwo and four carbon and one or two, preferably two, oxygen or sulfur,preferably oxygen, atoms.

In some embodiments, Y is C(O)NR¹⁰R¹² or NR¹⁰R¹² and R¹⁰ and R¹² canform a ring wherein the ring contains the N of NR¹⁰R¹² and optionallyone further heteroatom selected from O and N, wherein if the one furtherheteroatom is N, it is optionally substituted by R⁸, wherein the ring,R¹⁰ and R¹² can form is a non-aromatic ring, preferably a non-aromaticring containing between four and seven atoms e.g. between three and sixcarbon atoms and the N of NR¹⁰R¹², or between three and five carbonatoms and the N of NR¹⁰R¹² and optionally one further heteroatomselected from O and N, wherein if the one further heteroatom is N, it isoptionally substituted by R⁸.

In some embodiments, R² is C(O)NR¹⁵R¹⁵ and both R¹⁵ can form a ringwherein the ring contains the N of NR¹⁵R¹⁵ and optionally one furtherheteroatom selected from O and N, wherein if the one further heteroatomis N, it is optionally substituted by R⁸, wherein the ring, both R¹⁵ canform is a non-aromatic ring, preferably a non-aromatic ring containingbetween four and seven atoms e.g. between three and six carbon atoms andthe N of NR¹⁵R¹⁵, or between three and five carbon atoms and the N ofNR¹⁵R¹⁵ and optionally one further heteroatom selected from O and N,wherein if the one further heteroatom is N, it is optionally substitutedby R⁸.

In some embodiments, the integer n of S(O)_(n)R⁸ is 1 or 2.

In some embodiments, Y is selected from H, C(O)NR¹⁰R¹², C(O)OR¹⁰,R¹⁰NC(O)NR¹⁰R¹², OC(O)R¹⁰, OC(O)NR¹⁰R¹², S(O)_(n)R⁸ wherein n is 0, 1 or2, SO₂NR¹⁰R¹², NR¹⁰SO₂R¹⁰, NR¹⁰R¹², HNCOR⁸, CN, C₃₋₇-cycloalkyloptionally containing a heteroatom in the ring selected from O and Nwherein if the heteroatom is N it is optionally substituted by R⁸;S-aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl, O-aryl,S-heteroaryl, O-heteroaryl are optionally substituted by one or more R⁹or R¹⁴; or aryl, heteroaryl wherein the aryl or heteroaryl is optionallysubstituted by one or more of R⁸; and wherein Y can form a ring with anypart of X or R⁵, wherein the ring optionally contains a carbonyl group;with the proviso that when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² canform a ring wherein the ring contains the N of NR¹⁰R¹² and optionallyone further heteroatom selected from O and N, wherein if the one furtherheteroatom is N, it is optionally substituted by R⁸.

In some embodiments, Y is selected from NR¹⁰R¹² and C₃₋₇-cycloalkyloptionally containing a heteroatom in the ring selected from O and Nwherein if the heteroatom is N it is optionally substituted by R⁸; andwherein Y can form a ring with any part of X or R⁵; with the provisothat when Y is NR¹⁰R¹², R¹⁰ and R¹² can form a ring wherein the ringcontains the N of NR¹⁰R¹² and optionally one further heteroatom selectedfrom O and N, wherein if the one further heteroatom is N, it isoptionally substituted by R⁸.

In some embodiments, R⁵ is selected from H and C₁₋₇ alkyl; wherein C₁₋₇alkyl of R⁵ can form a ring with any part of Y;

X is selected from a bond and C₁₋₇ alkanediyl, and wherein C₁₋₇alkanediyl of X can form a ring with any part of Y;

Y is selected from NR¹⁰R¹² and C₃₋₇-cycloalkyl optionally containing ahetero atom in the ring wherein the heteroatom is N and is optionallysubstituted by R⁸ wherein R⁸ is C₁₋₇ alkyl; wherein Y can form a ringwith any part of C₁₋₇ alkanediyl of X or with any part of C₁₋₇ alkyl ofR⁵; with the proviso that when Y is NR¹⁰R¹², R¹⁰ and R¹² can form a ringwherein the ring contains the N of NR¹⁰R¹² and optionally one furtherheteroatom selected from O and N, wherein if the one further heteroatomis N, it is optionally substituted by R⁸; and

R¹⁰ and R¹² are each independently selected from H, C₁₋₇ alkyl, C₃₋₇cycloalkyl, or C₁₋₃ alkyl-aryl, all these groups optionally substitutedby halogen.

In some embodiments, R⁵ is selected from C₁₋₇ alkyl, OR, or SR⁸; whereinC₁₋₇ alkyl, OR⁸ or SR⁸ of R⁵ can form a ring with any part of X;

X is selected from —O—C₁₋₇ alkanediyl, —S—C₁₋₇ alkanediyl, or C₁₋₇alkanediyl, and wherein —O—C₁₋₇ alkanediyl, —S—C₁₋₇ alkanediyl or C₁₋₇alkanediyl of X can form a ring with any part of R⁵; and

Y is NR¹⁰R¹², wherein R¹⁰ and R¹² can form a ring wherein the ringcontains the N of NR¹⁰R¹² and optionally one further heteroatom selectedfrom O and N, wherein if the one further heteroatom is N, it isoptionally substituted by R⁸.

In some embodiments, R⁵ is OR⁸, wherein R⁸ of OR⁸ is C₁₋₇ alkyl, whereinOR⁸ of R⁵ can form a ring with any part of X;

X is —O—C₁₋₇ alkanediyl and wherein —O—C₁₋₇ alkanediyl of X can form aring with any part of R⁵; and

Y is NR¹⁰R¹² wherein R¹⁰ and R¹² can form a ring wherein the ringcontains the N of NR¹⁰R¹² and four or five carbon atoms.

In some embodiments, Y is aryl or heteroaryl, wherein the aryl or theheteroaryl is optionally substituted by one or more of R⁸; orS-heteroaryl, wherein the S-heteroaryl is optionally substituted by oneor more R⁴.

In some embodiments, Y is heteroaryl, wherein the heteroaryl isoptionally substituted by one or more of R⁸; or S-heteroaryl, whereinthe S-heteroaryl is optionally substituted by one or more R¹⁴.

In some embodiments, R⁵ is selected from H and C₁₋₇ alkyl;

X is selected from a bond and C₁₋₇ alkanediyl; and

Y is aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by one or more of R⁸; or S-heteroaryl wherein theS-heteroaryl is optionally substituted by one or more R¹⁴.

In some embodiments, R⁵ is selected from H and C₁₋₇ alkyl;

X is selected from a bond and C₁₋₇ alkanediyl; and

Y is heteroaryl, wherein the heteroaryl is optionally substituted by oneor more of R⁸; or S-heteroaryl wherein the S-heteroaryl is optionallysubstituted by one or more R¹⁴.

In some embodiments, R⁵ is selected from H and C₁₋₇ alkyl;

X is selected from a bond and C₁₋₇ alkanediyl; and

Y is aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by one of R⁸ wherein R⁸ is selected from C₁₋₇alkyl, C₂₋₇ alkenyl, or C₃₋₇ cycloalkyl; or S-heteroaryl wherein theS-heteroaryl is optionally substituted by one of R¹⁴ wherein R¹⁴ isselected from C₁₋₇ alkyl, C₂₋₇ alkenyl, or C₃₋₇ cycloalkyl.

In some embodiments, R⁵ is selected from H and C₁₋₇ alkyl;

X is selected from a bond and C₁₋₇ alkanediyl; and

Y is heteroaryl, wherein the heteroaryl is optionally substituted by oneof R⁸ wherein R⁸ is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₃₋₇cycloalky; or S-heteroaryl wherein the S-heteroaryl is optionallysubstituted by one of R¹⁴ wherein R¹⁴ is selected from C₁₋₇ alkyl, C₂₋₇alkenyl, C₃₋₇ cycloalkyl.

In some embodiments, the compound is of any one of Formulae (Va), (Vb),(Vc), or (Vd):

or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3,and R¹, R², R³, R⁴, R⁶, R⁷, R¹⁰ and R¹² are as described herein.

In some embodiments, the compound is of Formula (Va) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3,and R¹, R², R³, R⁴, R⁶, R⁷, R¹⁰ and R¹² are as described herein.

In some embodiments, the compound is of Formula (Vb) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3,and R¹, R², R³, R⁴, R⁶, R⁷, R¹⁰ and R¹² are as described herein.

In some embodiments, the compound is of Formula (Vc) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3,and R¹, R², R³, R⁴, R⁶, R⁷, R¹⁰ and R¹² are as described herein.

In some embodiments, the compound is of Formula (Vd) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3,and R¹, R², R³, R⁴, R⁶, R⁷, R¹⁰ and R¹² are as described herein.

In some embodiments, R⁵ is H and X—Y is

In some embodiments, the compound is of any one of Formulae (VIa),(VIb), (VIc), or (VId):

or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3,and R¹, R², R³, R⁴, R⁶, R⁷, R¹⁰ and R¹² are as described herein.

In some embodiments, the compound is of Formula (VIa) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3,and R¹, R², R³, R⁴, R⁶, R⁷, R¹⁰ and R¹² are as described herein.

In some embodiments, the compound is of Formula (VIb) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3,and R¹, R², R³, R⁴, R⁶, R⁷, R¹⁰ and R¹² are as described herein.

In some embodiments, the compound is of Formula (VIc) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3,and R¹, R², R³, R⁴, R⁶, R⁷, R¹⁰ and R¹² are as described herein.

In some embodiments, the compound is of Formula (VId) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3,and R¹, R², R³, R⁴, R⁶, R⁷, R¹⁰ and R¹² are as described herein.

In some embodiments, Y is C(O)NR¹⁰R¹², wherein R¹⁰ and R¹² can form aring wherein the ring contains the N of NR¹⁰R¹² and optionally onefurther heteroatom selected from O and N, wherein if the one furtherheteroatom is N, it is optionally substituted by R⁸.

In some embodiments, R⁵ is H and X—Y is

In some embodiments, R⁵ is selected from H and C₁₋₇ alkyl;

X is selected from a bond and C₁₋₇ alkanediyl;

Y is C(O)NR¹⁰R¹², wherein R¹⁰ and R¹² can form a ring wherein the ringcontains the N of NR¹⁰R¹² and optionally one further heteroatom selectedfrom O and N, wherein if the one further heteroatom is N, it isoptionally substituted by R⁸; and

R¹⁰ and R¹² are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₃₋₇ cycloalkyl, or C₁₋₃ alkyl-aryl.

In some embodiments, Y is selected from S-aryl, O-aryl, S-heteroaryl, orO-heteroaryl, wherein the S-aryl, O-aryl, S-heteroaryl, or O-heteroarylare optionally substituted by one or more R⁹ or R¹⁴.

In some embodiments, Y is selected from O-aryl and O-heteroaryl, whereinthe O-aryl and O-heteroaryl are optionally substituted by one or more R⁹or R¹⁴.

In some embodiments, Y is selected from S-aryl, O-aryl, S-heteroaryl, orO-heteroaryl, wherein the S-aryl, O-aryl, S-heteroaryl, or O-heteroarylare optionally substituted by one or more R⁹; wherein R⁹ is selectedfrom H, C₁₋₅ alkyl, halogen, C₁₋₅ alkyl-NR⁸R¹¹, C₁₋₅ alkyl-C(O)OR⁸, C₁₋₅alkyl-C(O)NR⁸R¹¹, CN, C(O)R⁸, C(O)NR⁸R¹¹, C(O)OR⁸, and OR⁸.

In some embodiments, R⁵ is selected from H and C₁₋₇ alkyl;

X is selected from a bond and C₁₋₇ alkanediyl; and

Y is selected from O-aryl and O-heteroaryl, wherein the O-aryl andO-heteroaryl is optionally substituted by one or more R⁹; wherein R⁹ isselected from H, C₁₋₅ alkyl, halogen, C₁₋₅ alkyl-NR⁸R¹¹, C₁₋₅alkyl-C(O)NR⁸R¹¹, C₁₋₅ alkyl-C(O)OR⁸, CN, C(O)R⁸, C(O)NR⁸R¹¹, C(O)OR⁸,and OR⁸.

In some embodiments, Y is C(O)OR¹⁰.

In some embodiments, R⁵ is selected from H and C₁₋₇ alkyl;

X is selected from a bond and C₁₋₇ alkanediyl;

Y is C(O)OR¹⁰; and

R¹⁰ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₃alkyl-aryl, or C₁₋₃ alkyl-heteroaryl, all these groups optionallysubstituted by OR⁸.

In some embodiments, Y is H.

In some embodiments, R⁵ is C₁₋₇ alkyl; X is a bond; and Y is H.

In some embodiments, Y is CN.

In some embodiments, R⁵ is H; X is C₁₋₇ alkanediyl; and Y is CN.

In some embodiments, Y is selected from H, C(O)NR¹⁰R¹², C(O)OR¹⁰,NR¹⁰R¹², CN, C₃₋₇-cycloalkyl optionally containing a hetero atom in thering selected from O and N wherein if the heteroatom is N it isoptionally substituted by R⁸; S-aryl, O-aryl, S-heteroaryl, O-heteroarylwherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionallysubstituted by one or more R⁹ or R¹⁴; aryl, or heteroaryl wherein thearyl or heteroaryl is optionally substituted by one or more of R⁸; andwherein Y can form a ring with any part of X or R⁵, wherein the ringoptionally contains a carbonyl group; with the proviso that when Y isC(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² can form a ring wherein the ringcontains the N of NR¹⁰R¹² and optionally one further heteroatom selectedfrom O and N, wherein if the one further heteroatom is N, it isoptionally substituted by R⁸.

In some embodiments, the compound is a compound of Formula (I) orFormula (Ia), wherein:

R¹ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R² is selected from H, C(O)R¹⁴, C(O)NR¹⁵R¹⁵, C(O)OR, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₅alkyl-OR⁸, C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₅alkyl-NHCOR¹³, or C₁₋₃ alkyl substituted by aryl or heteroaryl, whereinthe aryl or the heteroaryl is optionally substituted by halogen, C₁₋₄alkyl or C₃₋₅ cycloalkyl; with the proviso that when R² is C(O)NR¹⁵R¹⁵,both R¹⁵ can form a ring wherein the ring contains the N of NR¹⁵R¹⁵ andoptionally one further heteroatom selected from O and N, wherein if theone further heteroatom is N, it is optionally substituted by R⁸;

R³ and R⁷ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, alloptionally substituted by halogen, OR⁸, NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁴ is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁵ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, C₁₋₃ alkyl-OR⁸, or SR⁸; and whereinR⁵ can form a ring with any part of X or Y, wherein the ring optionallycontains a carbonyl group;

R⁶ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, all optionally substituted by halogen,OR⁸, NR⁸R¹¹; C₁₋₃ alkyl substituted by C(O)NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; or isimidazolidinone;

R⁸ and R¹¹ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl;

X is selected from a bond, C₁₋₇ alkanediyl, C₂₋₇ alkenediyl, C₂₋₇alkynediyl, C₃₋₆ cycloalkanediyl, C₄₋₆ cycloalkenediyl, —O—, C₁₋₃alkanediyl-O—, —O—C₁₋₇ alkanediyl, C₁₋₃ alkanediyl-O—C₁₋₇ alkanediyl,C₁₋₇ heteroalkanediyl, or —S—C₁₋₇ alkanediyl; and wherein X can form aring with any part of R⁵ or Y, wherein the ring optionally contains acarbonyl group;

Y is selected from H, C(O)NR¹⁰R¹², C(O)OR¹⁰, NR¹⁰R¹², CN,C₃₋₇-cycloalkyl optionally containing a hetero atom in the ring selectedfrom O and N wherein if the heteroatom is N it is optionally substitutedby R⁸; S-aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl,O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one ormore R⁹ or R¹⁴; or aryl, heteroaryl wherein the aryl or heteroaryl isoptionally substituted by one or more of R⁸; and wherein Y can form aring with any part of X or R⁵, wherein the ring optionally contains acarbonyl group; with the proviso that when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹²,R¹⁰ and R¹² can form a ring wherein the ring contains the N of NR¹⁰R¹²and optionally one further heteroatom selected from O and N, wherein ifthe one further heteroatom is N, it is optionally substituted by R⁸;

R⁹ is selected from H, halogen, C₁₋₅ alkyl, C₂₋₅ alkenyl, C₂₋₅ alkynyl,C₃₋₅ cycloalkyl, halogen, C₁₋₅ alkyl-OR⁸, C₁₋₅ alkyl-SR⁸, C₁₋₅alkyl-NR⁸R¹¹, C₁₋₅ alkyl-C(O)OR⁸, C₁₋₅ alkyl-C(O)NR⁸R¹¹, C₁₋₅alkyl-C(O)R¹⁰, CN, C(O)R⁸, C(O)NR⁸R¹¹, C(O)OR⁸, NR⁸C(O)NR⁸R¹¹,OC(O)NR⁸R¹¹, SO₂NR⁸R¹¹, NR⁸SO₂R⁸, OR⁸, NR⁸R¹¹, or S(O)_(n)R⁸ wherein nis 0, 1 or 2;

R¹⁰ and R¹² are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₃alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₃ alkyl-aryl, or C₁₋₃alkyl-heteroaryl, all these groups optionally substituted by halogen,OR⁸, or NR⁸R¹¹;

R¹³ is C₁₋₅ alkyl substituted by a bicyclic ring optionally containingat least one heteroatom and a carbonyl group;

R¹⁴ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; each R¹⁵ is independentlyselected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, or C₁₋₃ alkyl-OR⁸.

In some embodiments, Y is selected from H, C(O)NR¹⁰R¹², C(O)OR¹⁰,NR¹⁰R¹², CN, C₃₋₇-cycloalkyl optionally containing a heteroatom in thering selected from O and N wherein if the heteroatom is N it isoptionally substituted by R⁸; S-aryl, O-aryl, S-heteroaryl, O-heteroarylwherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionallysubstituted by one or more R⁹ or R¹⁴; or aryl, heteroaryl wherein thearyl or heteroaryl is optionally substituted by one or more of R⁸; andwherein, when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², Y can form a ring with anypart of X or R⁵, wherein the ring optionally contains a carbonyl group;with the proviso that when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² canform a ring wherein the ring contains the N of NR¹⁰R¹² and optionallyone further heteroatom selected from O and N, wherein if the one furtherheteroatom is N, it is optionally substituted by R⁸.

In some embodiments, the compound is a compound of Formula (I) orFormula (Ia), wherein:

R¹ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R² is selected from H, C(O)R¹⁴, C(O)NR¹⁵R¹⁵, C(O)OR, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₅alkyl-OR⁸, C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₅alkyl-NHCOR¹³, or C₁₋₃ alkyl substituted by aryl or heteroaryl, whereinthe aryl or the heteroaryl is optionally substituted by halogen, C₁₋₄alkyl or C₃₋₅ cycloalkyl; with the proviso that when R² is C(O)NR¹⁵R¹⁵,both R¹⁵ can form a ring wherein the ring contains the N of NR¹⁵R¹⁵ andoptionally one further heteroatom selected from O and N, wherein if theone further heteroatom is N, it is optionally substituted by R⁸;

R³ and R⁷ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, alloptionally substituted by halogen, OR⁸, NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁴ is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁵ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, C₁₋₃ alkyl-OR⁸, or SR⁸; and whereinR⁵ can form a ring with any part of X or, when Y is C(O)NR¹⁰R¹² orNR¹⁰R¹², R⁵ can form a ring with any part of Y, wherein the ringoptionally contains a carbonyl group;

R⁶ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, all optionally substituted by halogen,OR⁸, NR⁸R¹¹; C₁₋₃ alkyl substituted by C(O)NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; or isimidazolidinone;

R⁸ and R¹¹ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl;

X is selected from a bond, C₁₋₇ alkanediyl, C₂₋₇ alkenediyl, C₂₋₇alkynediyl, C₃₋₆ cycloalkanediyl, C₄₋₆ cycloalkenediyl, —O—, C₁₋₃alkanediyl-O—, —O—C₁₋₇ alkanediyl, C₁₋₃ alkanediyl-O—C₁₋₇ alkanediyl,C₁₋₇ heteroalkanediyl, or —S—C₁₋₇ alkanediyl; and wherein X can form aring with any part of R⁵ or, when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², X canform a ring with any part of Y, wherein the ring optionally contains acarbonyl group;

Y is selected from H, C(O)NR¹⁰R¹², C(O)OR¹⁰, NR¹⁰R¹², CN,C₃₋₇-cycloalkyl optionally containing a heteroatom in the ring selectedfrom O and N wherein if the heteroatom is N it is optionally substitutedby R⁸; S-aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl,O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one ormore R⁹ or R¹⁴; or aryl, heteroaryl wherein the aryl or heteroaryl isoptionally substituted by one or more of R⁸; and wherein, when Y isC(O)NR¹⁰R¹² or NR¹⁰R¹², Y can form a ring with any part of X or R⁵,wherein the ring optionally contains a carbonyl group; with the provisothat when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² can form a ringwherein the ring contains the N of NR¹⁰R¹² and optionally one furtherheteroatom selected from O and N, wherein if the one further heteroatomis N, it is optionally substituted by R⁸;

R⁹ is selected from H, halogen, C₁₋₅ alkyl, C₂₋₅ alkenyl, C₂₋₅ alkynyl,C₃₋₅ cycloalkyl, C₁₋₅ alkyl-OR⁸, C₁₋₅ alkyl-SR⁸, C₁₋₅ alkyl-NR⁸R¹¹, C₁₋₅alkyl-C(O)OR⁸, C₁₋₅ alkyl-C(O)NR⁸R¹¹, C₁₋₅ alkyl-C(O)R¹⁰, CN, C(O)R⁸,C(O)NR⁸R¹¹, C(O)OR⁸, NR⁸C(O)NR⁸R¹¹, OC(O)NR⁸R¹¹, SO₂NR⁸R¹¹, NR⁸SO₂R⁸,OR⁸, NR⁸R¹¹, or S(O)_(n)R⁸ wherein n is 0, 1 or 2;

R¹⁰ and R¹² are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₃alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₃ alkyl-aryl, or C₁₋₃alkyl-heteroaryl, all these groups optionally substituted by halogen,OR⁸, or NR⁸R¹¹;

R¹³ is C₁₋₅ alkyl substituted by a bicyclic ring optionally containingat least one heteroatom and a carbonyl group;

R¹⁴ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

each R¹⁵ is independently selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, or C₁₋₃alkyl-OR⁸.

In some embodiments, the compound is a compound of Formula (I) orFormula (Ia), wherein:

R¹ is selected from C₃₋₇ alkyl, C₃₋₇ cycloalkyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl;

R² is selected from H, C(O)R¹⁴, C₁₋₇ alkyl, C₃₋₇ cycloalkyl, C₁₋₅alkyl-OR; C₁₋₅ alkyl-NHCOR¹³ wherein R¹³ ispentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3-one; orC₁₋₃ alkyl substituted by aryl, wherein the aryl is optionallysubstituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R³ and R⁷ are H;

R⁴ is selected from C₃₋₇ alkyl, C₃₋₇ cycloalkyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl;

R⁵ is selected from H, C₁₋₇ alkyl, or OR⁸; and wherein C₁₋₇ alkyl or OR⁸of R⁵ can form a ring with any part of X or, when Y is C(O)NR¹⁰R¹² orNR¹⁰R¹², C₁₋₇ alkyl of R⁵ can form a ring with any part of Y, whereinthe ring optionally contains a carbonyl group;

R⁶ is H, C₁₋₇ alkyl, or imidazolidinone;

R⁸ and R¹¹ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, and C₃₋₇ cycloalkyl;

X is selected from a bond, —O—C₁₋₇ alkanediyl and C₁₋₇ alkanediyl; andwherein —O—C₁₋₇ alkanediyl or C₁₋₇ alkanediyl of X can form a ring withany part of R⁵ or, when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², C₁₋₇ alkanediyl ofX can form a ring with any part of Y, wherein the ring optionallycontains a carbonyl group;

Y is selected from H, C(O)NR¹⁰R¹², C(O)OR¹⁰, NR¹⁰R¹², CN,C₃₋₇-cycloalkyl optionally containing a heteroatom in the ring selectedfrom O and N wherein if the heteroatom is N it is optionally substitutedby R⁸; O-aryl, S-heteroaryl, O-heteroaryl wherein the O-aryl or theO-heteroaryl are optionally substituted by one or more R⁹ and whereinthe S-heteroaryl is optionally substituted by one or more R¹⁴; or aryl,heteroaryl wherein the aryl or the heteroaryl is optionally substitutedby one or more of R⁸; and wherein, when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², Ycan form a ring with any part of C₁₋₇ alkanediyl of X or any part ofC₁₋₇ alkyl of R⁵, wherein the ring optionally contains a carbonyl group;with the proviso that when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² canform a ring wherein the ring contains the N of NR¹⁰R¹² and optionallyone further heteroatom selected from O and N, wherein if the one furtherheteroatom is N, it is optionally substituted by R⁸;

R⁹ is selected from H, C₁₋₅ alkyl, halogen, C₁₋₅ alkyl-NR⁸R¹¹, C₁₋₅alkyl-C(O)OR⁸, C₁₋₅ alkyl-C(O)NR⁸R¹¹, CN, C(O)R⁸, C(O)NR⁸R¹¹, C(O)OR⁸,and OR⁸;

R¹⁰ and R¹² are each independently selected selected from H, C₁₋₇ alkyl,C₂₋₇ alkenyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₃ alkanediyl-O—C₁₋₃alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₃ alkyl-aryl, or C₁₋₃ alkyl-heteroaryl,all these groups optionally substituted by halogen or OR⁸; and

R¹⁴ is C₁₋₇ alkyl.

In some embodiments, Y is selected from H, C(O)NR¹⁰R¹², C(O)OR¹⁰,NR¹⁰R¹², C₃₋₇-cycloalkyl optionally containing a hetero atom in the ringselected from O and N wherein if the heteroatom is N it is optionallysubstituted by R⁸; S-aryl, O-aryl, S-heteroaryl, O-heteroaryl whereinthe S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionallysubstituted by one or more R⁹ or R¹⁴; or aryl, heteroaryl wherein thearyl or heteroaryl is optionally substituted by one or more of R⁸; andwherein Y can form a ring with any part of X or R⁵, wherein the ringoptionally contains a carbonyl group; with the proviso that when Y isC(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² can form a ring wherein the ringcontains the N of NR¹⁰R¹² and optionally one further heteroatom selectedfrom O and N, wherein if the one further heteroatom is N, it isoptionally substituted by R⁸.

In some embodiments, Y is selected from H, C(O)NR¹⁰R¹², C(O)OR¹⁰,NR¹⁰R¹², C₃₋₇-cycloalkyl optionally containing a hetero atom in the ringselected from O and N wherein if the heteroatom is N it is optionallysubstituted by R⁸; S-aryl, O-aryl, S-heteroaryl, O-heteroaryl whereinthe S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionallysubstituted by one or more R⁹ or R¹⁴; or aryl, heteroaryl wherein thearyl or heteroaryl is optionally substituted by one or more of R⁸; andwherein, when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², Y can form a ring with anypart of X or R⁵, wherein the ring optionally contains a carbonyl group;with the proviso that when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² canform a ring wherein the ring contains the N of NR¹⁰R¹² and optionallyone further heteroatom selected from O and N, wherein if the one furtherheteroatom is N, it is optionally substituted by R⁸.

In some embodiments, the compound is a compound of Formula (I) orFormula (Ia), wherein:

R¹ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R² is selected from H, C(O)R¹⁴, C(O)NR¹⁵R¹⁵, C(O)OR, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₅alkyl-OR⁸, C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₅alkyl-NHCOR¹³, or C₁₋₃ alkyl substituted by aryl or heteroaryl, whereinthe aryl or the heteroaryl is optionally substituted by halogen, C₁₋₄alkyl or C₃₋₅ cycloalkyl; with the proviso that when R² is C(O)NR¹⁵R¹⁵,both R¹⁵ can form a ring wherein the ring contains the N of NR¹⁵R¹⁵ andoptionally one further heteroatom selected from O and N, wherein if theone further heteroatom is N, it is optionally substituted by R⁸;

R³ and R⁷ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, alloptionally substituted by halogen, OR⁸, NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁴ is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁵ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, C₁₋₃ alkyl-OR⁸, or SR⁸; and whereinR⁵ can form a ring with any part of X or Y, wherein the ring optionallycontains a carbonyl group;

R⁶ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, all optionally substituted by halogen,OR⁸, NR⁸R¹¹; C₁₋₃ alkyl substituted by C(O)NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; or isimidazolidinone;

R⁸ and R¹¹ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl;

X is selected from a bond, C₁₋₇ alkanediyl, C₂₋₇ alkenediyl, C₂₋₇alkynediyl, C₃₋₆ cycloalkanediyl, C₄₋₆ cycloalkenediyl, —O—, C₁₋₃alkanediyl-O—, —O—C₁₋₇ alkanediyl, C₁₋₃ alkanediyl-O—C₁₋₇ alkanediyl,C₁₋₇ heteroalkanediyl, or —S—C₁₋₇ alkanediyl; and wherein X can form aring with any part of R⁵ or Y, wherein the ring optionally contains acarbonyl group;

Y is selected from H, C(O)NR¹⁰R¹², C(O)OR¹⁰, NR¹⁰R¹², C₃₋₇-cycloalkyloptionally containing a heteroatom in the ring selected from O and Nwherein if the heteroatom is N it is optionally substituted by R⁸;S-aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl, O-aryl,S-heteroaryl, O-heteroaryl are optionally substituted by one or more R⁹or R¹⁴; or aryl, heteroaryl wherein the aryl or heteroaryl is optionallysubstituted by one or more of R⁸; and wherein Y can form a ring with anypart of X or R⁵, wherein the ring optionally contains a carbonyl group;with the proviso that when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² canform a ring wherein the ring contains the N of NR¹⁰R¹² and optionallyone further heteroatom selected from O and N, wherein if the one furtherheteroatom is N, it is optionally substituted by R⁸;

R⁹ is selected from H, halogen, C₁₋₅ alkyl, C₂₋₅ alkenyl, C₂₋₅ alkynyl,C₃₋₅ cycloalkyl, halogen, C₁₋₅ alkyl-OR⁸, C₁₋₅ alkyl-SR⁸, C₁₋₅alkyl-NR⁸R¹¹, C₁₋₅ alkyl-C(O)NR⁸R¹¹, C₁₋₅ alkyl-C(O)OR⁸, C₁₋₅alkyl-C(O)R¹⁰, CN, C(O)R⁸, C(O)NR⁸R¹¹, C(O)OR⁸, NR⁸C(O)NR⁸R¹¹,OC(O)NR⁸R¹¹, SO₂NR⁸R¹¹, NR⁸SO₂R⁸, OR⁸, NR⁸R¹¹, or S(O)_(n)R⁸ wherein nis 0, 1 or 2;

R¹⁰ and R¹² are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₃alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₃ alkyl-aryl, or C₁₋₃alkyl-heteroaryl, all these groups optionally substituted by halogen,OR⁸, or NR⁸R¹¹;

R¹³ is C₁₋₅ alkyl substituted by a bicyclic ring optionally containingat least one heteroatom and a carbonyl group;

R¹⁴ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; and

each R¹⁵ is independently selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, or C₁₋₃alkyl-OR⁸.

In some embodiments, the compound is a compound of Formula (I) orFormula (Ia), wherein:

R¹ is selected from C₃₋₇ alkyl, C₃₋₇ cycloalkyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl;

R² is selected from H, C(O)R¹⁴, C₁₋₇ alkyl, C₃₋₇ cycloalkyl, C₁₋₅alkyl-OR⁸; C₁₋₅ alkyl-NHCOR¹³ wherein R¹³ ispentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3-one; orC₁₋₃ alkyl substituted by aryl, wherein the aryl is optionallysubstituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R³ and R⁷ are H;

R⁴ is selected from C₃₋₇ alkyl, C₃₋₇ cycloalkyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl;

R⁵ is selected from H, C₁₋₇ alkyl, or OR⁸; and wherein C₁₋₇ alkyl or OR⁸of R⁵ can form a ring with any part of X or, when Y is C(O)NR¹⁰R¹² orNR¹⁰R¹², C₁₋₇ alkyl of R⁵ can form a ring with any part of Y, whereinthe ring optionally contains a carbonyl group;

R⁶ is H, C₁₋₇ alkyl, or imidazolidinone;

R⁸ and R¹¹ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, and C₃₋₇ cycloalkyl;

X is selected from a bond, —O—C₁₋₇ alkanediyl and C₁₋₇ alkanediyl; andwherein —O—C₁₋₇ alkanediyl or C₁₋₇ alkanediyl of X can form a ring withany part of R⁵ or, when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², C₁₋₇ alkanediyl ofX can form a ring with any part of Y, wherein the ring optionallycontains a carbonyl group;

Y is selected from H, C(O)NR¹⁰R¹², C(O)OR¹⁰, NR¹⁰R¹², C₃₋₇-cycloalkyloptionally containing a heteroatom in the ring selected from O and Nwherein if the heteroatom is N it is optionally substituted by R⁸;O-aryl, S-heteroaryl, O-heteroaryl wherein the O-aryl or theO-heteroaryl are optionally substituted by one or more R⁹ and whereinthe S-heteroaryl is optionally substituted by one or more R¹⁴; or aryl,heteroaryl wherein the aryl or the heteroaryl is optionally substitutedby one or more of R⁸; and wherein, when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², Ycan form a ring with any part of C₁₋₇ alkanediyl of X or any part ofC₁₋₇ alkyl of R⁵, wherein the ring optionally contains a carbonyl group;with the proviso that when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² canform a ring wherein the ring contains the N of NR¹⁰R¹² and optionallyone further heteroatom selected from O and N, wherein if the one furtherheteroatom is N, it is optionally substituted by R⁸;

R⁹ is selected from H, C₁₋₅ alkyl, halogen, C₁₋₅ alkyl-NR⁸R¹¹, C₁₋₅alkyl-C(O)NR⁸R¹¹, C₁₋₅ alkyl-C(O)OR⁸, CN, C(O)R⁸, C(O)NR⁸R¹¹, C(O)OR⁸,and OR⁸;

R¹⁰ and R¹² are each independently selected selected from H, C₁₋₇ alkyl,C₂₋₇ alkenyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₃ alkanediyl-O—C₁₋₃alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₃ alkyl-aryl, or C₁₋₃ alkyl-heteroaryl,all these groups optionally substituted by halogen or OR⁸; and

R¹⁴ is C₁₋₇ alkyl.

In some embodiments, Y is selected from C(O)NR¹⁰R¹², C(O)OR¹⁰, NR¹⁰R¹²,C₃₋₇-cycloalkyl optionally containing a heteroatom in the ring selectedfrom O and N wherein if the heteroatom is N it is optionally substitutedby R⁸; S-aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl,O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one ormore R⁹ or R¹⁴; or aryl, heteroaryl wherein the aryl or heteroaryl isoptionally substituted by one or more of R⁸; and wherein Y can form aring with any part of X or R⁵, wherein the ring optionally contains acarbonyl group; with the proviso that when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹²,R¹⁰ and R¹² can form a ring wherein the ring contains the N of NR¹⁰R¹²and optionally one further heteroatom selected from O and N, wherein ifthe one further heteroatom is N, it is optionally substituted by R⁸.

In some embodiments, Y is selected from C(O)NR¹⁰R¹², C(O)OR¹⁰, NR¹⁰R¹²,C₃₋₇-cycloalkyl optionally containing a hetero atom in the ring selectedfrom O and N wherein if the heteroatom is N it is optionally substitutedby R⁸; S-aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl,O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one ormore R⁹ or R¹⁴; or aryl, heteroaryl wherein the aryl or heteroaryl isoptionally substituted by one or more of R⁸; and wherein, when Y isC(O)NR¹⁰R¹² or NR¹⁰R¹², Y can form a ring with any part of X or R⁵,wherein the ring optionally contains a carbonyl group; with the provisothat when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² can form a ringwherein the ring contains the N of NR¹⁰R¹² and optionally one furtherheteroatom selected from O and N, wherein if the one further heteroatomis N, it is optionally substituted by R⁸.

In some embodiments, the compound is a compound of Formula (I) orFormula (Ia), wherein:

R¹ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R² is selected from H, C(O)R¹⁴, C(O)NR¹⁵R¹⁵, C(O)OR, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₅alkyl-OR⁸, C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₅alkyl-NHCOR¹³, or C₁₋₃ alkyl substituted by aryl or heteroaryl, whereinthe aryl or the heteroaryl is optionally substituted by halogen, C₁₋₄alkyl or C₃₋₅ cycloalkyl; with the proviso that when R² is C(O)NR¹⁵R¹⁵,both R¹⁵ can form a ring wherein the ring contains the N of NR¹⁵R¹⁵ andoptionally one further heteroatom selected from O and N, wherein if theone further heteroatom is N, it is optionally substituted by R⁸;

R³ and R⁷ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, alloptionally substituted by halogen, OR⁸, NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁴ is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁵ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, C₁₋₃ alkyl-OR⁸, or SR⁸; and whereinR⁵ can form a ring with any part of X or Y, wherein the ring optionallycontains a carbonyl group;

R⁶ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, all optionally substituted by halogen,OR⁸, NR⁸R¹¹; C₁₋₃ alkyl substituted by C(O)NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; or isimidazolidinone;

R⁸ and R¹¹ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl;

X is selected from a bond, C₁₋₇ alkanediyl, C₂₋₇ alkenediyl, C₂₋₇alkynediyl, C₃₋₆ cycloalkanediyl, C₄₋₆ cycloalkenediyl, —O—, C₁₋₃alkanediyl-O—, —O—C₁₋₇ alkanediyl, C₁₋₃ alkanediyl-O—C₁₋₇ alkanediyl,C₁₋₇ heteroalkanediyl, or —S—C₁₋₇ alkanediyl; and wherein X can form aring with any part of R⁵ or Y, wherein the ring optionally contains acarbonyl group;

Y is selected from C(O)NR¹⁰R¹², C(O)OR¹⁰, NR¹⁰R¹², C₃₋₇-cycloalkyloptionally containing a heteroatom in the ring selected from O and Nwherein if the heteroatom is N it is optionally substituted by R⁸;S-aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl, O-aryl,S-heteroaryl, O-heteroaryl are optionally substituted by one or more R⁹or R¹⁴; or aryl, heteroaryl wherein the aryl or heteroaryl is optionallysubstituted by one or more of R⁸; and wherein Y can form a ring with anypart of X or R⁵, wherein the ring optionally contains a carbonyl group;with the proviso that when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² canform a ring wherein the ring contains the N of NR¹⁰R¹² and optionallyone further heteroatom selected from O and N, wherein if the one furtherheteroatom is N, it is optionally substituted by R⁸;

R⁹ is selected from H, halogen, C₁₋₅ alkyl, C₂₋₅ alkenyl, C₂₋₅ alkynyl,C₃₋₅ cycloalkyl, C₁₋₅ alkyl-OR⁸, C₁₋₅ alkyl-SR⁸, C₁₋₅ alkyl-NR⁸R¹¹, C₁₋₅alkyl-C(O)OR⁸, C₁₋₅ alkyl-C(O)NR⁸R¹¹, C₁₋₅ alkyl-C(O)R¹⁰, CN, C(O)R⁸,C(O)NR⁸R¹¹, C(O)OR⁸, NR⁸C(O)NR⁸R¹¹, OC(O)NR⁸R¹¹, SO₂NR⁸R¹¹, NR⁸SO₂R⁸,OR⁸, NR⁸R¹¹, or S(O)_(n)R⁸ wherein n is 0, 1 or 2;

R¹⁰ and R¹² are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₃alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₃ alkyl-aryl, or C₁₋₃alkyl-heteroaryl, all these groups optionally substituted by halogen,OR⁸, or NR⁸R¹¹;

R¹³ is C₁₋₅ alkyl substituted by a bicyclic ring optionally containingat least one heteroatom and a carbonyl group;

R¹⁴ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; and

each R¹⁵ is independently selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, or C₁₋₃alkyl-OR⁸.

In some embodiments, the compound is a compound of Formula (I) orFormula (Ia), wherein:

R¹ is selected from C₃₋₇ alkyl, C₃₋₇ cycloalkyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl;

R² is selected from H, C(O)R¹⁴, C₁₋₇ alkyl, C₃₋₇ cycloalkyl, C₁₋₅alkyl-OR⁸; C₁₋₅ alkyl-NHCOR¹³ wherein R¹³ ispentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3-one; orC₁₋₃ alkyl substituted by aryl, wherein the aryl is optionallysubstituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R³ and R⁷ are H;

R⁴ is selected from C₃₋₇ alkyl, C₃₋₇ cycloalkyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl;

R⁵ is selected from H, C₁₋₇ alkyl, or OR⁸; and wherein C₁₋₇ alkyl or OR⁸of R⁵ can form a ring with any part of X or, when Y is C(O)NR¹⁰R¹² orNR¹⁰R¹², C₁₋₇ alkyl of R⁵ can form a ring with any part of Y, whereinthe ring optionally contains a carbonyl group;

R⁶ is H or C₁₋₇ alkyl;

R⁸ and R¹¹ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, and C₃₋₇ cycloalkyl;

X is selected from a bond, —O—C₁₋₇ alkanediyl and C₁₋₇ alkanediyl; andwherein —O—C₁₋₇ alkanediyl or C₁₋₇ alkanediyl of X can form a ring withany part of R⁵ or, when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², C₁₋₇ alkanediyl ofX can form a ring with any part of Y, wherein the ring optionallycontains a carbonyl group;

Y is selected from C(O)NR¹⁰R¹², C(O)OR¹⁰, NR¹⁰R¹², C₃₋₇-cycloalkyloptionally containing a heteroatom in the ring selected from O and Nwherein if the heteroatom is N it is optionally substituted by R⁸;O-aryl, S-heteroaryl, O-heteroaryl wherein the O-aryl or theO-heteroaryl are optionally substituted by one or more R⁹ and whereinthe S-heteroaryl is optionally substituted by one or more R¹⁴; or aryl,heteroaryl wherein the aryl or the heteroaryl is optionally substitutedby one or more of R⁸; and wherein, when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², Ycan form a ring with any part of C₁₋₇ alkanediyl of X or any part ofC₁₋₇ alkyl of R⁵, wherein the ring optionally contains a carbonyl group;with the proviso that when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² canform a ring wherein the ring contains the N of NR¹⁰R¹² and optionallyone further heteroatom selected from O and N, wherein if the one furtherheteroatom is N, it is optionally substituted by R⁸;

R⁹ is selected from H, C₁₋₅ alkyl, halogen, C₁₋₅ alkyl-NR⁸R¹¹, C₁₋₅alkyl-C(O)OR⁸, C₁₋₅ alkyl-C(O)NR⁸R¹¹, CN, C(O)R⁸, C(O)NR⁸R¹¹, C(O)OR⁸,and OR⁸;

R¹⁰ and R¹² are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₃ alkanediyl-O—C₁₋₃alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₃ alkyl-aryl, or C₁₋₃ alkyl-heteroaryl,all these groups optionally substituted by halogen or OR⁸; and

R¹⁴ is C₁₋₇ alkyl.

In some embodiments, Y is selected from C(O)NR¹⁰R¹², C(O)OR¹⁰, NR¹⁰R¹²,C₃₋₇-cycloalkyl optionally containing a heteroatom in the ring selectedfrom O and N wherein if the heteroatom is N it is optionally substitutedby R⁸; S-aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl,O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one ormore R⁹ or R¹⁴; or heteroaryl wherein the heteroaryl is optionallysubstituted by one or more of R⁸; and wherein Y can form a ring with anypart of X or R⁵, wherein the ring optionally contains a carbonyl group;with the proviso that when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² canform a ring wherein the ring contains the N of NR¹⁰R¹² and optionallyone further heteroatom selected from O and N, wherein if the one furtherheteroatom is N, it is optionally substituted by R⁸.

In some embodiments, Y is selected from C(O)NR¹⁰R¹², C(O)OR¹⁰, NR¹⁰R¹²,C₃₋₇-cycloalkyl optionally containing a heteroatom in the ring selectedfrom O and N wherein if the heteroatom is N it is optionally substitutedby R⁸; S-aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl,O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one ormore R⁹ or R¹⁴; or heteroaryl wherein the heteroaryl is optionallysubstituted by one or more of R⁸; and wherein, when Y is C(O)NR¹⁰R¹² orNR¹⁰R¹², Y can form a ring with any part of X or R⁵, wherein the ringoptionally contains a carbonyl group; with the proviso that when Y isC(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² can form a ring wherein the ringcontains the N of NR¹⁰R¹² and optionally one further heteroatom selectedfrom O and N, wherein if the one further heteroatom is N, it isoptionally substituted by R⁸.

In some embodiments, the compound is a compound of Formula (I) orFormula (Ia), wherein:

R¹ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R² is selected from H, C(O)R¹⁴, C(O)NR¹⁵R¹⁵, C(O)OR, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₅alkyl-OR⁸, C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₅alkyl-NHCOR¹³, or C₁₋₃ alkyl substituted by aryl or heteroaryl, whereinthe aryl or the heteroaryl is optionally substituted by halogen, C₁₋₄alkyl or C₃₋₅ cycloalkyl; with the proviso that when R² is C(O)NR¹⁵R¹⁵,both R¹⁵ can form a ring wherein the ring contains the N of NR¹⁵R¹⁵ andoptionally one further heteroatom selected from O and N, wherein if theone further heteroatom is N, it is optionally substituted by R⁸;

R³ and R⁷ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, alloptionally substituted by halogen, OR⁸, NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁴ is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁵ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, C₁₋₃ alkyl-OR⁸, or SR⁸; and whereinR⁵ can form a ring with any part of X or Y, wherein the ring optionallycontains a carbonyl group;

R⁶ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, all optionally substituted by halogen,OR⁸, NR⁸R¹¹; C₁₋₃ alkyl substituted by C(O)NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; or isimidazolidinone;

R⁸ and R¹¹ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl;

X is selected from a bond, C₁₋₇ alkanediyl, C₂₋₇ alkenediyl, C₂₋₇alkynediyl, C₃₋₆ cycloalkanediyl, C₄₋₆ cycloalkenediyl, —O—, C₁₋₃alkanediyl-O—, —O—C₁₋₇ alkanediyl, C₁₋₃ alkanediyl-O—C₁₋₇ alkanediyl,C₁₋₇ heteroalkanediyl, or —S—C₁₋₇ alkanediyl; and wherein X can form aring with any part of R⁵ or Y, wherein the ring optionally contains acarbonyl group;

Y is selected from C(O)NR¹⁰R¹², C(O)OR¹⁰, NR¹⁰R¹², C₃₋₇-cycloalkyloptionally containing a heteroatom in the ring selected from O and Nwherein if the heteroatom is N it is optionally substituted by R⁸;S-aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl, O-aryl,S-heteroaryl, O-heteroaryl are optionally substituted by one or more R⁹or R¹⁴; or heteroaryl wherein the heteroaryl is optionally substitutedby one or more of R⁸; and wherein Y can form a ring with any part of Xor R⁵, wherein the ring optionally contains a carbonyl group; with theproviso that when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² can form aring wherein the ring contains the N of NR¹⁰R¹² and optionally onefurther heteroatom selected from O and N, wherein if the one furtherheteroatom is N, it is optionally substituted by R⁸;

R⁹ is selected from H, halogen, C₁₋₅ alkyl, C₂₋₅ alkenyl, C₂₋₅ alkynyl,C₃₋₅ cycloalkyl, C₁₋₅ alkyl-OR⁸, C₁₋₅ alkyl-SR⁸, C₁₋₅ alkyl-NR⁸R¹¹, C₁₋₅alkyl-C(O)NR⁸R¹¹, C₁₋₅ alkyl-C(O)OR⁸, C₁₋₅ alkyl-C(O)R¹⁰, CN, C(O)R⁸,C(O)NR⁸R¹¹, C(O)OR⁸, NR⁸C(O)NR⁸R¹¹, OC(O)NR⁸R¹¹, SO₂NR⁸R¹¹, NR⁸SO₂R⁸,OR⁸, NR⁸R¹¹, or S(O)_(n)R⁸ wherein n is 0, 1 or 2;

wherein R¹⁰ and R¹² are each independently selected from H, C₁₋₇ alkyl,C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₃alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₃ alkyl-aryl, or C₁₋₃alkyl-heteroaryl, all these groups optionally substituted by halogen,OR⁸, or NR⁸R¹¹;

R¹³ is C₁₋₅ alkyl substituted by a bicyclic ring optionally containingat least one heteroatom and a carbonyl group;

R¹⁴ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; and

each R¹⁵ is independently selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, or C₁₋₃alkyl-OR⁸.

In some embodiments, the compound is a compound of Formula (I) orFormula (Ia), wherein:

R¹ is selected from C₃₋₇ alkyl, C₃₋₇ cycloalkyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl;

R² is selected from H, C(O)R¹⁴, C₁₋₇ alkyl, C₃₋₇ cycloalkyl, C₁₋₅alkyl-OR; C₁₋₅ alkyl-NHCOR¹³ wherein R¹³ ispentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3-one; orC₁₋₃ alkyl substituted by aryl, wherein the aryl is optionallysubstituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R³ and R⁷ are H;

R⁴ is selected from C₃₋₇ alkyl, C₃₋₇ cycloalkyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl;

R⁵ is selected from H, C₁₋₇ alkyl, or OR⁸; and wherein C₁₋₇ alkyl or OR⁸of R⁵ can form a ring with any part of X or, when Y is C(O)NR¹⁰R¹² orNR¹⁰R¹², C₁₋₇ alkyl of R⁵ can form a ring with any part of Y, whereinthe ring optionally contains a carbonyl group;

R⁶ is H or C₁₋₇ alkyl;

R⁸ and R¹¹ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, and C₃₋₇ cycloalkyl;

X is selected from a bond, —O—C₁₋₇ alkanediyl and C₁₋₇ alkanediyl; andwherein —O—C₁₋₇ alkanediyl or C₁₋₇ alkanediyl of X can form a ring withany part of R⁵ or, when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², C₁₋₇ alkanediyl ofX can form a ring with any part of Y, wherein the ring optionallycontains a carbonyl group;

Y is selected from C(O)NR¹⁰R¹², C(O)OR¹⁰, NR¹⁰R¹², C₃₋₇-cycloalkyloptionally containing a heteroatom in the ring selected from O and Nwherein if the heteroatom is N it is optionally substituted by R⁸;O-aryl, S-heteroaryl, O-heteroaryl wherein the O-aryl or theO-heteroaryl are optionally substituted by one or more R⁹ and whereinthe S-heteroaryl is optionally substituted by one or more R¹⁴; orheteroaryl wherein the heteroaryl is optionally substituted by one ormore of R⁸; and wherein, when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², Y can form aring with any part of C₁₋₇ alkanediyl of X or any part of C₁₋₇ alkyl ofR⁵, wherein the ring optionally contains a carbonyl group; with theproviso that when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² can form aring wherein the ring contains the N of NR¹⁰R¹² and optionally onefurther heteroatom selected from O and N, wherein if the one furtherheteroatom is N, it is optionally substituted by R⁸;

R⁹ is selected from H, C₁₋₅ alkyl, halogen, C₁₋₅ alkyl-NR⁸R¹¹, C₁₋₅alkyl-C(O)NR⁸R¹¹, C₁₋₅ alkyl-C(O)OR⁸, CN, C(O)R⁸, C(O)NR⁸R¹¹, C(O)OR⁸,and OR⁸;

R¹⁰ and R¹² are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₃ alkanediyl-O—C₁₋₃alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₃ alkyl-aryl, or C₁₋₃ alkyl-heteroaryl,all these groups optionally substituted by halogen or OR⁸; and

R¹⁴ is C₁₋₇ alkyl.

In some embodiments, Y is selected from C(O)NR¹⁰R¹², NR¹⁰R¹²,C₃₋₇-cycloalkyl optionally containing a heteroatom in the ring selectedfrom O and N wherein if the heteroatom is N it is optionally substitutedby R⁸; S-aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl,O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one ormore R⁹ or R¹⁴; or heteroaryl wherein the heteroaryl is optionallysubstituted by one or more of R⁸; and wherein Y can form a ring with anypart of X or R⁵, wherein the ring optionally contains a carbonyl group;with the proviso that when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² canform a ring wherein the ring contains the N of NR¹⁰R¹² and optionallyone further heteroatom selected from O and N, wherein if the one furtherheteroatom is N, it is optionally substituted by R⁸.

In some embodiments, Y is selected from C(O)NR¹⁰R¹², NR¹⁰R¹²,C₃₋₇-cycloalkyl optionally containing a heteroatom in the ring selectedfrom O and N wherein if the heteroatom is N it is optionally substitutedby R⁸; S-aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl,O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one ormore R⁹ or R¹⁴; or heteroaryl wherein the heteroaryl is optionallysubstituted by one or more of R⁸; and wherein, when Y is C(O)NR¹⁰R¹² orNR¹⁰R¹², Y can form a ring with any part of X or R⁵, wherein the ringoptionally contains a carbonyl group; with the proviso that when Y isC(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² can form a ring wherein the ringcontains the N of NR¹⁰R¹² and optionally one further heteroatom selectedfrom O and N, wherein if the one further heteroatom is N, it isoptionally substituted by R⁸.

In some embodiments, the compound is a compound of Formula (I) orFormula (Ia), wherein:

R¹ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R² is selected from H, C(O)R¹⁴, C(O)NR¹⁵R¹⁵, C(O)OR¹⁵, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₅alkyl-OR⁸, C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₅alkyl-NHCOR¹³, or C₁₋₃ alkyl substituted by aryl or heteroaryl, whereinthe aryl or the heteroaryl is optionally substituted by halogen, C₁₋₄alkyl or C₃₋₅ cycloalkyl; with the proviso that when R² is C(O)NR¹⁵R¹⁵,both R¹⁵ can form a ring wherein the ring contains the N of NR¹⁵R¹⁵ andoptionally one further heteroatom selected from O and N, wherein if theone further heteroatom is N, it is optionally substituted by R⁸;

R³ and R⁷ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, alloptionally substituted by halogen, OR⁸, NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁴ is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁵ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, C₁₋₃ alkyl-OR⁸, or SR⁸; and whereinR⁵ can form a ring with any part of X or Y, wherein the ring optionallycontains a carbonyl group;

R⁶ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, all optionally substituted by halogen,OR⁸, NR⁸R¹¹; C₁₋₃ alkyl substituted by C(O)NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; or isimidazolidinone;

R⁸ and R¹¹ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl;

X is selected from a bond, C₁₋₇ alkanediyl, C₂₋₇ alkenediyl, C₂₋₇alkynediyl, C₃₋₆ cycloalkanediyl, C₄₋₆ cycloalkenediyl, —O—, C₁₋₃alkanediyl-O—, —O—C₁₋₇ alkanediyl, C₁₋₃ alkanediyl-O—C₁₋₇ alkanediyl,C₁₋₇ heteroalkanediyl, or —S—C₁₋₇ alkanediyl; and wherein X can form aring with any part of R⁵ or Y, wherein the ring optionally contains acarbonyl group;

Y is selected from C(O)NR¹⁰R¹², NR¹⁰R¹², C₃₋₇-cycloalkyl optionallycontaining a heteroatom in the ring selected from O and N wherein if theheteroatom is N it is optionally substituted by R⁸; S-aryl, O-aryl,S-heteroaryl, O-heteroaryl wherein the S-aryl, O-aryl, S-heteroaryl,O-heteroaryl are optionally substituted by one or more R⁹ or R¹⁴; orheteroaryl wherein the heteroaryl is optionally substituted by one ormore of R⁸; and wherein Y can form a ring with any part of X or R⁵,wherein the ring optionally contains a carbonyl group; with the provisothat when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² can form a ringwherein the ring contains the N of NR¹⁰R¹² and optionally one furtherheteroatom selected from O and N, wherein if the one further heteroatomis N, it is optionally substituted by R⁸;

R⁹ is selected from H, halogen, C₁₋₅ alkyl, C₂₋₅ alkenyl, C₂₋₅ alkynyl,C₃₋₅ cycloalkyl, C₁₋₅ alkyl-OR⁸, C₁₋₅ alkyl-SR⁸, C₁₋₅ alkyl-NR⁸R¹¹, C₁₋₅alkyl-C(O)OR⁸, C₁₋₅ alkyl-C(O)NR⁸R¹¹, C₁₋₅ alkyl-C(O)R¹⁰, CN, C(O)R⁸,C(O)NR⁸R¹¹, C(O)OR⁸, NR⁸C(O)NR⁸R¹¹, OC(O)NR⁸R¹¹, SO₂NR⁸R¹¹, NR⁸SO₂R⁸,OR⁸, NR⁸R¹¹, or S(O)_(n)R⁸ wherein n is 0, 1 or 2;

R¹⁰ and R¹² are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₃alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₃ alkyl-aryl, or C₁₋₃alkyl-heteroaryl, all these groups optionally substituted by halogen,OR⁸, or NR⁸R¹¹;

R¹³ is C₁₋₅ alkyl substituted by a bicyclic ring optionally containingat least one heteroatom and a carbonyl group;

R¹⁴ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; and

each R¹⁵ is independently selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, C₁₋₃ alkyl-OR⁸.

In some embodiments, the compound is a compound of Formula (I) orFormula (Ia), wherein:

R¹ is selected from C₃₋₇ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkyl substitutedby aryl or heteroaryl;

R² is selected from H, C(O)R¹⁴, C₁₋₇ alkyl, C₃₋₇ cycloalkyl, C₁₋₅alkyl-OR; C₁₋₅ alkyl-NHCOR¹³ wherein R¹³ ispentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3-one; orC₁₋₃ alkyl substituted by aryl, wherein the aryl is optionallysubstituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R³ and R⁷ are H;

R⁴ is selected from C₃₋₇ alkyl, C₃₋₇ cycloalkyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl;

R⁵ is selected from H, C₁₋₇ alkyl, or OR⁸; and wherein C₁₋₇ alkyl or OR⁸of R⁵ can form a ring with any part of X or, when Y is C(O)NR¹⁰R¹² orNR¹⁰R¹², C₁₋₇ alkyl of R⁵ can form a ring with any part of Y, whereinthe ring optionally contains a carbonyl group;

R⁶ is H or C₁₋₇ alkyl;

R⁸ and R¹¹ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, and C₃₋₇ cycloalkyl;

X is selected from a bond, —O—C₁₋₇ alkanediyl and C₁₋₇ alkanediyl; andwherein —O—C₁₋₇ alkanediyl or C₁₋₇ alkanediyl of X can form a ring withany part of R⁵ or, when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², C₁₋₇ alkanediyl ofX can form a ring with any part of Y, wherein the ring optionallycontains a carbonyl group;

Y is selected from C(O)NR¹⁰R¹², NR¹⁰R¹², C₃₋₇-cycloalkyl optionallycontaining a heteroatom in the ring selected from O and N wherein if theheteroatom is N it is optionally substituted by R⁸; O-aryl,S-heteroaryl, O-heteroaryl wherein the O-aryl or the O-heteroaryl areoptionally substituted by one or more R⁹ and wherein the S-heteroaryl isoptionally substituted by one or more R¹⁴; or heteroaryl wherein theheteroaryl is optionally substituted by one or more of R⁸; and wherein,when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², Y can form a ring with any part ofC₁₋₇ alkanediyl of X or any part of C₁₋₇ alkyl of R⁵, wherein the ringoptionally contains a carbonyl group; with the proviso that when Y isC(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² can form a ring wherein the ringcontains the N of NR¹⁰R¹² and optionally one further heteroatom selectedfrom O and N, wherein if the one further heteroatom is N, it isoptionally substituted by R⁸;

R⁹ is selected from H, C₁₋₅ alkyl, halogen, C₁₋₅ alkyl-NR⁸R¹¹, C₁₋₅alkyl-C(O)NR⁸R¹¹, C₁₋₅ alkyl-C(O)OR⁸, CN, C(O)R⁸, C(O)NR⁸R¹¹, C(O)OR⁸,and OR⁸;

R¹⁰ and R¹² are each independently selected from H, C₁₋₇ alkyl, C₃₋₇cycloalkyl, C₁₋₃ alkyl-aryl, all these groups optionally substituted byhalogen; and

R¹⁴ is C₁₋₇ alkyl.

In some embodiments, Y is selected from NR¹⁰R¹², C₃₋₇-cycloalkyloptionally containing a heteroatom in the ring selected from O and Nwherein if the heteroatom is N it is optionally substituted by R⁸;S-heteroaryl, wherein the S-heteroaryl is optionally substituted by oneor more R¹⁴; aryl, or heteroaryl wherein the aryl or heteroaryl isoptionally substituted by one or more of R⁸; and wherein Y can form aring with any part of X or R⁵, wherein the ring optionally contains acarbonyl group; with the proviso that when Y is NR¹⁰R¹², R¹⁰ and R¹² canform a ring wherein the ring contains the N of NR¹⁰R¹² and optionallyone further heteroatom selected from O and N, wherein if the one furtherheteroatom is N, it is optionally substituted by R⁸.

In some embodiments, Y is selected from NR¹⁰R¹², C₃₋₇-cycloalkyloptionally containing a heteroatom in the ring selected from O and Nwherein if the heteroatom is N it is optionally substituted by R⁸;S-heteroaryl, wherein the S-heteroaryl is optionally substituted by oneor more R¹⁴; aryl, or heteroaryl wherein the aryl or heteroaryl isoptionally substituted by one or more of R⁸; and wherein, when Y isNR¹⁰R¹², Y can form a ring with any part of X or R⁵, wherein the ringoptionally contains a carbonyl group; with the proviso that when Y isNR¹⁰R¹², R¹⁰ and R¹² can form a ring wherein the ring contains the N ofNR¹⁰R¹² and optionally one further heteroatom selected from O and N,wherein if the one further heteroatom is N, it is optionally substitutedby R⁸.

In some embodiments, the compound is a compound of Formula (I) orFormula (Ia), wherein:

R¹ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R² is selected from H, C(O)R¹⁴, C(O)NR¹⁵R¹⁵, C(O)OR, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₅alkyl-OR⁸, C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₅alkyl-NHCOR¹³, or C₁₋₃ alkyl substituted by aryl or heteroaryl, whereinthe aryl or the heteroaryl is optionally substituted by halogen, C₁₋₄alkyl or C₃₋₅ cycloalkyl; with the proviso that when R² is C(O)NR¹⁵R¹⁵,both R¹⁵ can form a ring wherein the ring contains the N of NR¹⁵R¹⁵ andoptionally one further heteroatom selected from O and N, wherein if theone further heteroatom is N, it is optionally substituted by R⁸;

R³ and R⁷ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, alloptionally substituted by halogen, OR⁸, NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁴ is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁵ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, C₁₋₃ alkyl-OR⁸, or SR⁸; and whereinR⁵ can form a ring with any part of X or Y, wherein the ring optionallycontains a carbonyl group;

R⁶ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, all optionally substituted by halogen,OR⁸, NR⁸R¹¹; C₁₋₃ alkyl substituted by C(O)NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; or isimidazolidinone;

R⁸ and R¹¹ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl;

X is selected from a bond, C₁₋₇ alkanediyl, C₂₋₇ alkenediyl, C₂₋₇alkynediyl, C₃₋₆ cycloalkanediyl, C₄₋₆ cycloalkenediyl, —O—, C₁₋₃alkanediyl-O—, —O—C₁₋₇ alkanediyl, C₁₋₃ alkanediyl-O—C₁₋₇ alkanediyl,C₁₋₇ heteroalkanediyl, or —S—C₁₋₇ alkanediyl; and wherein X can form aring with any part of R⁵ or Y, wherein the ring optionally contains acarbonyl group;

Y is selected from NR¹⁰R¹², C₃₋₇-cycloalkyl optionally containing aheteroatom in the ring selected from O and N wherein if the heteroatomis N it is optionally substituted by R⁸; S-heteroaryl, wherein theS-heteroaryl is optionally substituted by one or R¹⁴; aryl, orheteroaryl wherein the aryl or heteroaryl is optionally substituted byone or more of R⁸; and wherein Y can form a ring with any part of X orR⁵, wherein the ring optionally contains a carbonyl group; with theproviso that when Y is NR¹⁰R¹², R¹⁰ and R¹² can form a ring wherein thering contains the N of NR¹⁰R¹² and optionally one further heteroatomselected from O and N, wherein if the one further heteroatom is N, it isoptionally substituted by R⁸;

R¹⁰ and R¹² are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₃alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₃ alkyl-aryl, or C₁₋₃alkyl-heteroaryl, all these groups optionally substituted by halogen,OR⁸, or NR⁸R¹¹;

R¹³ is C₁₋₅ alkyl substituted by a bicyclic ring optionally containingat least one heteroatom and a carbonyl group;

R¹⁴ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; and R¹⁵ is independentlyselected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, or C₁₋₃ alkyl-OR⁸.

In some embodiments, the compound is a compound of Formula (I) orFormula (Ia), wherein:

R¹ is selected from C₃₋₇ alkyl, C₃₋₇ cycloalkyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl;

R² is selected from H, C(O)R¹⁴, C₁₋₇ alkyl, C₃₋₇ cycloalkyl, C₁₋₅alkyl-OR⁸; C₁₋₅ alkyl-NHCOR¹³ wherein R¹³ ispentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3-one; orC₁₋₃ alkyl substituted by aryl, wherein the aryl is optionallysubstituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R³ and R⁷ are H;

R⁴ is selected from C₃₋₇ alkyl, C₃₋₇ cycloalkyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl;

R⁵ is selected from H, C₁₋₇ alkyl, or OR⁸; and wherein C₁₋₇ alkyl or OR⁸of R⁵ can form a ring with any part of X or, when Y is NR¹⁰R¹², C₁₋₇alkyl of R⁵ can form a ring with any part of Y;

R⁶ is H;

R⁸ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, and C₃₋₇ cycloalkyl;

X is selected from a bond, —O—C₁₋₇ alkanediyl and C₁₋₇ alkanediyl; andwherein —O—C₁₋₇ alkanediyl or C₁₋₇ alkanediyl of X can form a ring withany part of R⁵ or, when Y is NR¹⁰R¹², C₁₋₇ alkanediyl of X can form aring with any part of Y;

Y is selected from NR¹⁰R¹², C₃₋₇-cycloalkyl optionally containing aheteroatom in the ring selected from O and N wherein if the heteroatomis N it is optionally substituted by R⁸, wherein R⁸ is C₁₋₇ alkyl;S-heteroaryl wherein the S-heteroaryl is optionally substituted by oneor more R¹⁴; aryl, or heteroaryl wherein the aryl or the heteroaryl isoptionally substituted by one or more of R⁸; and wherein, when Y isNR¹⁰R¹², Y can form a ring with any part of C₁₋₇ alkanediyl of X or anypart of C₁₋₇ alkyl of R⁵; with the proviso that when Y is NR¹⁰R¹², R¹⁰and R¹² can form a ring wherein the ring contains the N of NR¹⁰R¹² andoptionally one further heteroatom selected from O and N, wherein if theone further heteroatom is N, it is optionally substituted by R⁸;

R¹⁰ and R¹² are each independently selected from H, C₁₋₇ alkyl, C₃₋₇cycloalkyl, or C₁₋₃ alkyl-aryl, all these groups optionally substitutedby halogen; and

R¹⁴ is C₁₋₇ alkyl.

In some embodiments, the aryl, the heteroaryl or the S-heteroaryl groupof any of the compounds of the present disclosure are preferablyselected from the group consisting of phenyl, imidazole, pyridine andtriazole, more preferably selected from the group consisting of phenyl,imidazole and pyridine.

In some embodiments, Y is selected from NR¹⁰R¹², C₃₋₇-cycloalkyloptionally containing a heteroatom in the ring selected from O and Nwherein if the heteroatom is N it is optionally substituted by R⁸;S-heteroaryl, wherein the S-heteroaryl is optionally substituted by oneor more R¹⁴; or heteroaryl wherein the heteroaryl is optionallysubstituted by one or more of R⁸; and wherein Y can form a ring with anypart of X or R⁵, wherein the ring optionally contains a carbonyl group;with the proviso that when Y is NR¹⁰R¹², R¹⁰ and R¹² can form a ringwherein the ring contains the N of NR¹⁰R¹² and optionally one furtherheteroatom selected from O and N, wherein if the one further heteroatomis N, it is optionally substituted by R⁸.

In some embodiments, Y is selected from NR¹⁰R¹², C₃₋₇-cycloalkyloptionally containing a heteroatom in the ring selected from O and Nwherein if the heteroatom is N it is optionally substituted by R⁸;S-heteroaryl, wherein the S-heteroaryl is optionally substituted by oneor R¹⁴; or heteroaryl wherein the heteroaryl is optionally substitutedby one or more of R⁸; and wherein, when Y is NR¹⁰R¹², Y can form a ringwith any part of X or R⁵, wherein the ring optionally contains acarbonyl group; with the proviso that when Y is NR¹⁰R¹², R¹⁰ and R¹² canform a ring wherein the ring contains the N of NR¹⁰R¹² and optionallyone further heteroatom selected from O and N, wherein if the one furtherheteroatom is N, it is optionally substituted by R⁸.

In some embodiments, the compound is a compound of Formula (I) orFormula (Ia), wherein:

R¹ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R² is selected from H, C(O)R¹⁴, C(O)NR¹⁵R¹⁵, C(O)OR, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₅alkyl-OR⁸, C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₅alkyl-NHCOR¹³, or C₁₋₃ alkyl substituted by aryl or heteroaryl, whereinthe aryl or the heteroaryl is optionally substituted by halogen, C₁₋₄alkyl or C₃₋₅ cycloalkyl; with the proviso that when R² is C(O)NR¹⁵R¹⁵,both R¹⁵ can form a ring wherein the ring contains the N of NR¹⁵R¹⁵ andoptionally one further heteroatom selected from O and N, wherein if theone further heteroatom is N, it is optionally substituted by R⁸;

R³ and R⁷ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, alloptionally substituted by halogen, OR⁸, NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁴ is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁵ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, C₁₋₃ alkyl-OR⁸, or SR⁸; and whereinR⁵ can form a ring with any part of X or Y, wherein the ring optionallycontains a carbonyl group;

R⁶ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, all optionally substituted by halogen,OR⁸, NR⁸R¹¹; C₁₋₃ alkyl substituted by C(O)NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; or isimidazolidinone;

R⁸ and R¹¹ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl;

X is selected from a bond, C₁₋₇ alkanediyl, C₂₋₇ alkenediyl, C₂₋₇alkynediyl, C₃₋₆ cycloalkanediyl, C₄₋₆ cycloalkenediyl, —O—, C₁₋₃alkanediyl-O—, —O—C₁₋₇ alkanediyl, C₁₋₃ alkanediyl-O—C₁₋₇ alkanediyl,C₁₋₇ heteroalkanediyl, or —S—C₁₋₇ alkanediyl; and wherein X can form aring with any part of R⁵ or Y, wherein the ring optionally contains acarbonyl group;

Y is selected from NR¹⁰R¹², C₃₋₇-cycloalkyl optionally containing aheteroatom in the ring selected from O and N wherein if the heteroatomis N it is optionally substituted by R⁸; S-heteroaryl, wherein theS-heteroaryl is optionally substituted by one or R¹⁴; or heteroarylwherein the heteroaryl is optionally substituted by one or more of R⁸;and wherein Y can form a ring with any part of X or R⁵, wherein the ringoptionally contains a carbonyl group; with the proviso that when Y isNR¹⁰R¹², R¹⁰ and R¹² can form a ring wherein the ring contains the N ofNR¹⁰R¹² and optionally one further heteroatom selected from O and N,wherein if the one further heteroatom is N, it is optionally substitutedby R⁸;

R¹⁰ and R¹² are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₃alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₃ alkyl-aryl, or C₁₋₃alkyl-heteroaryl, all these groups optionally substituted by halogen,OR⁸, or NR⁸R¹¹;

R¹³ is C₁₋₅ alkyl substituted by a bicyclic ring optionally containingat least one heteroatom and a carbonyl group;

R¹⁴ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; and

each R¹⁵ is independently selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, or C₁₋₃alkyl-OR⁸.

In some embodiments, the compound is a compound of Formula (I) orFormula (Ia), wherein:

R¹ is selected from C₃₋₇ alkyl, C₃₋₇ cycloalkyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl;

R² is selected from H, C(O)R¹⁴, C₁₋₇ alkyl, C₃₋₇ cycloalkyl, C₁₋₅alkyl-OR⁸; C₁₋₅ alkyl-NHCOR¹³ wherein R¹³ ispentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3-one; orC₁₋₃ alkyl substituted by aryl, wherein the aryl is optionallysubstituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R³ and R⁷ are H;

R⁴ is selected from C₃₋₇ alkyl, C₃₋₇ cycloalkyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl;

R⁵ is selected from H, C₁₋₇ alkyl, or OR⁸; and wherein C₁₋₇ alkyl or OR⁸of R⁵ can form a ring with any part of X or, when Y is NR¹⁰R¹², C₁₋₇alkyl of R⁵ can form a ring with any part of Y;

R⁶ is H;

R⁸ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, and C₃₋₇ cycloalkyl;

X is selected from a bond, —O—C₁₋₇ alkanediyl and C₁₋₇ alkanediyl; andwherein —O—C₁₋₇ alkanediyl or C₁₋₇ alkanediyl of X can form a ring withany part of R⁵ or, when Y is NR¹⁰R¹², C₁₋₇ alkanediyl of X can form aring with any part of Y;

Y is selected from NR¹⁰R¹², C₃₋₇-cycloalkyl optionally containing aheteroatom in the ring selected from O and N wherein if the heteroatomis N it is optionally substituted by R⁸, wherein R⁸ is C₁₋₇ alkyl;S-heteroaryl wherein the S-heteroaryl is optionally substituted by oneor more R¹⁴; or heteroaryl wherein the heteroaryl is optionallysubstituted by one or more of R⁸; and wherein, when Y is NR¹⁰R¹², Y canform a ring with any part of C₁₋₇ alkanediyl of X or any part of C₁₋₇alkyl of R⁵; with the proviso that when Y is NR¹⁰R¹², R¹⁰ and R¹² canform a ring wherein the ring contains the N of NR¹⁰R¹² and optionallyone further heteroatom selected from O and N, wherein if the one furtherheteroatom is N, it is optionally substituted by R⁸; and

R¹⁴ is C₁₋₇ alkyl.

In some embodiments, the aryl, the heteroaryl or the S-heteroaryl groupof the compounds of the present disclosure are preferably selected fromthe group consisting of phenyl, imidazole, pyridine and triazole, morepreferably selected from the group consisting of phenyl, imidazole andpyridine.

In some embodiments, Y is selected from NR¹⁰R¹² and C₃₋₇-cycloalkyloptionally containing a heteroatom in the ring selected from O and Nwherein if the heteroatom is N it is optionally substituted by R⁸; andwherein Y can form a ring with any part of X or R⁵; with the provisothat when Y is NR¹⁰R¹², R¹⁰ and R¹² can form a ring wherein the ringcontains the N of NR¹⁰R¹² and optionally one further heteroatom selectedfrom O and N, wherein if the one further heteroatom is N, it isoptionally substituted by R⁸.

In some embodiments, Y is selected from NR¹⁰R¹² and C₃₋₇-cycloalkyloptionally containing a heteroatom in the ring selected from O and Nwherein if the heteroatom is N it is optionally substituted by R⁸; andwherein, when Y is NR¹⁰R¹², Y can form a ring with any part of X or R⁵;with the proviso that when Y is NR¹⁰R¹², R¹⁰ and R¹² can form a ringwherein the ring contains the N of NR¹⁰R¹² and optionally one furtherheteroatom selected from O and N, wherein if the one further heteroatomis N, it is optionally substituted by R⁸.

In some embodiments, the compound is a compound of Formula (I) orFormula (Ia), wherein:

R¹ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R² is selected from H, C(O)R¹⁴, C(O)NR¹⁵R¹⁵, C(O)OR, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₅alkyl-OR⁸, C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₅alkyl-NHCOR¹³, or C₁₋₃ alkyl substituted by aryl or heteroaryl, whereinthe aryl or the heteroaryl is optionally substituted by halogen, C₁₋₄alkyl or C₃₋₅ cycloalkyl; with the proviso that when R² is C(O)NR¹⁵R¹⁵,both R¹⁵ can form a ring wherein the ring contains the N of NR¹⁵R¹⁵ andoptionally one further heteroatom selected from O and N, wherein if theone further heteroatom is N, it is optionally substituted by R⁸;

R³ and R⁷ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, alloptionally substituted by halogen, OR⁸, NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁴ is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁵ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, C₁₋₃ alkyl-OR⁸, or SR⁸; and whereinR⁵ can form a ring with any part of X or Y, wherein the ring optionallycontains a carbonyl group;

R⁶ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, all optionally substituted by halogen,OR⁸, NR⁸R¹¹; C₁₋₃ alkyl substituted by C(O)NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; or isimidazolidinone;

R⁸ and R¹¹ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl;

X is selected from a bond, C₁₋₇ alkanediyl, C₂₋₇ alkenediyl, C₂₋₇alkynediyl, C₃₋₆ cycloalkanediyl, C₄₋₆ cycloalkenediyl, —O—, C₁₋₃alkanediyl-O—, —O—C₁₋₇ alkanediyl, C₁₋₃ alkanediyl-O—C₁₋₇ alkanediyl,C₁₋₇ heteroalkanediyl, or —S—C₁₋₇ alkanediyl; and wherein X can form aring with any part of R⁵ or Y, wherein the ring optionally contains acarbonyl group;

Y is selected from NR¹⁰R¹² and C₃₋₇-cycloalkyl optionally containing aheteroatom in the ring selected from O and N wherein if the heteroatomis N it is optionally substituted by R⁸; and wherein Y can form a ringwith any part of X or R⁵; with the proviso that when Y is NR¹⁰R¹², R¹⁰and R¹² can form a ring wherein the ring contains the N of NR¹⁰R¹² andoptionally one further heteroatom selected from O and N, wherein if theone further heteroatom is N, it is optionally substituted by R⁸;

R¹⁰ and R¹² are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₃alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₃ alkyl-aryl, or C₁₋₃alkyl-heteroaryl, all these groups optionally substituted by halogen,OR⁸, or NR⁸R¹¹;

R¹³ is C₁₋₅ alkyl substituted by a bicyclic ring optionally containingat least one heteroatom and a carbonyl group;

R¹⁴ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; and

each R¹⁵ is independently selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, or C₁₋₃alkyl-OR⁸.

In some embodiments, the compound is a compound of Formula (I) orFormula (Ia), wherein:

R¹ is selected from C₃₋₇ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkyl substitutedby aryl or heteroaryl;

R² is selected from H, C(O)R⁴, wherein R¹⁴ is C₁₋₇ alkyl; C₁₋₇ alkyl,C₃₋₇ cycloalkyl, C₁₋₅ alkyl-OR⁸; C₁₋₅ alkyl-NHCOR¹³ wherein R¹³ ispentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3-one; orC₁₋₃ alkyl substituted by aryl, wherein the aryl is optionallysubstituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R³ and R⁷ are H;

R⁴ is selected from C₃₋₇ alkyl, C₃₋₇ cycloalkyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl;

R⁵ is selected from H and C₁₋₇ alkyl; and wherein C₁₋₇ alkyl of R⁵ canform a ring with any part of Y;

R⁶ is H;

R⁸ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, and C₃₋₇ cycloalkyl;

X is selected from a bond and C₁₋₇ alkanediyl, and wherein C₁₋₇alkanediyl of X can form a ring with any part of Y;

Y is selected from NR¹⁰R¹² or C₃₋₇-cycloalkyl optionally containing aheteroatom in the ring selected from O and N wherein if the heteroatomis N it is optionally substituted by R⁸, wherein R⁸ is C₁₋₇ alkyl; andwherein, when Y is NR¹⁰R¹², Y can form a ring with any part of C₁₋₇alkanediyl of X or any part of C₁₋₇ alkyl of R⁵; with the proviso thatwhen Y is NR¹⁰R¹², R¹⁰ and R¹² can form a ring wherein the ring containsthe N of NR¹⁰R¹² and optionally one further heteroatom selected from Oand N, wherein if the one further heteroatom is N, it is optionallysubstituted by R⁸; and

R¹⁰ and R¹² are each independently selected from H, C₁₋₇ alkyl, C₃₋₇cycloalkyl, C₁₋₃ alkyl-aryl, all these groups optionally substituted byhalogen.

In some embodiments, the aryl or the heteroaryl group of the compoundsof the present disclosure are preferably selected from the groupconsisting of phenyl, imidazole, pyridine and triazole, more preferablyselected from the group consisting of phenyl, imidazole and pyridine.

In some embodiments, the compound is of any one of Formulae (VIIa),(VIIb), (VIIc), (VIId), (VIIe), or (VIIf):

or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein n8 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3,and R¹, R², R³, R⁴, R⁶, R⁷, and R⁸ are as described herein.

In some embodiments, the compound is of Formula (VIIa) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein n8 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3,and R¹, R², R³, R⁴, R⁶, R⁷, and R⁸ are as described herein.

In some embodiments, the compound is of Formula (VIIb) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein n8 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3,and R¹, R², R³, R⁴, R⁶, R⁷, and R⁸ are as described herein.

In some embodiments, the compound is of Formula (VIIc) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein n8 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3,and R¹, R², R³, R⁴, R⁶, R⁷, and R⁸ are as described herein.

In some embodiments, the compound is of Formula (VIId) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein n8 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3,and R¹, R², R³, R⁴, R⁶, R⁷, and R⁸ are as described herein.

In some embodiments, the compound is of Formula (VIIe) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein n8 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3,and R¹, R², R³, R⁴, R⁶, R⁷, and R⁸ are as described herein.

In some embodiments, the compound is of Formula (VIIf) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein n8 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3,and R¹, R², R³, R⁴, R⁶, R⁷, and R⁸ are as described herein.

In some embodiments, R⁵ is H and X—Y is

In some embodiments, Y is aryl or heteroaryl, wherein the aryl or theheteroaryl is optionally substituted by one or more of R⁸; orS-heteroaryl, wherein the S-heteroaryl is optionally substituted by oneor more R¹⁴.

In some embodiments, the compound is a compound of Formula (I) orFormula (Ia), wherein:

R¹ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R² is selected from H, C(O)R¹⁴, C(O)NR¹⁵R¹⁵, C(O)OR, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₅alkyl-OR⁸, C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₅alkyl-NHCOR¹³, or C₁₋₃ alkyl substituted by aryl or heteroaryl, whereinthe aryl or the heteroaryl is optionally substituted by halogen, C₁₋₄alkyl or C₃₋₅ cycloalkyl; with the proviso that when R² is C(O)NR¹⁵R¹⁵,both R¹⁵ can form a ring wherein the ring contains the N of NR¹⁵R¹⁵ andoptionally one further heteroatom selected from O and N, wherein if theone further heteroatom is N, it is optionally substituted by R⁸;

R³ and R⁷ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, alloptionally substituted by halogen, OR⁸, NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁴ is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁵ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, C₁₋₃ alkyl-OR⁸, or SR⁸;

R⁶ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, all optionally substituted by halogen,OR⁸, NR⁸R¹¹; C₁₋₃ alkyl substituted by C(O)NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; or isimidazolidinone;

R⁸ and R¹¹ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl;

X is selected from a bond, C₁₋₇ alkanediyl, C₂₋₇ alkenediyl, C₂₋₇alkynediyl, C₃₋₆ cycloalkanediyl, C₄₋₆ cycloalkenediyl, —O—, C₁₋₃alkanediyl-O—, —O—C₁₋₇ alkanediyl, C₁₋₃ alkanediyl-O—C₁₋₇ alkanediyl,C₁₋₇ heteroalkanediyl, or —S—C₁₋₇ alkanediyl;

Y is aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by one or more of R⁸; or S-heteroaryl, whereinthe S-heteroaryl is optionally substituted by one or more R¹⁴;

R¹³ is C₁₋₅ alkyl substituted by a bicyclic ring optionally containingat least one heteroatom and a carbonyl group;

R¹⁴ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; and

each R¹⁵ is independently selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, or C₁₋₃alkyl-OR⁸.

In some embodiments, the compound is a compound of Formula (I) orFormula (Ia), wherein:

R¹ is selected from C₃₋₇ alkyl, C₃₋₇ cycloalkyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl;

R² is selected from H, C(O)R¹⁴, C₁₋₇ alkyl, C₃₋₇ cycloalkyl, C₁₋₅alkyl-OR; C₁₋₅ alkyl-NHCOR¹³ wherein R¹³ ispentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3-one; orC₁₋₃ alkyl substituted by aryl, wherein the aryl is optionallysubstituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R³ and R⁷ are H;

R⁴ is selected from C₃₋₇ alkyl, C₃₋₇ cycloalkyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl;

R⁵ is selected from H and C₁₋₇ alkyl;

R⁶ is H;

R⁸ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, and C₃₋₇ cycloalkyl;

X is selected from a bond and C₁₋₇ alkanediyl;

Y is aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by one or more of R⁸; or S-heteroaryl, whereinthe S-heteroaryl is optionally substituted by one or more R¹⁴; and

R¹⁴ is C₁₋₇ alkyl.

In some embodiments, the aryl, the heteroaryl or the S-heteroaryl groupof any of the compounds of the present disclosure are preferablyselected from the group consisting of phenyl, imidazole, pyridine andtriazole, more preferably selected from the group consisting of phenyl,imidazole and pyridine.

In some embodiments, Y is heteroaryl, wherein the heteroaryl isoptionally substituted by one or more of R⁸; or S-heteroaryl, whereinthe S-heteroaryl is optionally substituted by one or more R¹⁴.

In some embodiments, the compound is a compound of Formula (I) orFormula (Ia), wherein:

R¹ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R² is selected from H, C(O)R¹⁴, C(O)NR¹⁵R¹⁵, C(O)OR¹⁵, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₅alkyl-OR⁸, C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₅alkyl-NHCOR¹³, or C₁₋₃ alkyl substituted by aryl or heteroaryl, whereinthe aryl or the heteroaryl is optionally substituted by halogen, C₁₋₄alkyl or C₃₋₅ cycloalkyl; with the proviso that when R² is C(O)NR¹⁵R¹⁵,both R¹⁵ can form a ring wherein the ring contains the N of NR¹⁵R¹⁵ andoptionally one further heteroatom selected from O and N, wherein if theone further heteroatom is N, it is optionally substituted by R⁸;

R³ and R⁷ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, alloptionally substituted by halogen, OR⁸, NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁴ is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁵ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, C₁₋₃ alkyl-OR⁸, or SR⁸;

R⁶ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, all optionally substituted by halogen,OR⁸, NR⁸R¹¹; C₁₋₃ alkyl substituted by C(O)NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; or isimidazolidinone;

R⁸ and R¹¹ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl;

X is selected from a bond, C₁₋₇ alkanediyl, C₂₋₇ alkenediyl, C₂₋₇alkynediyl, C₃₋₆ cycloalkanediyl, C₄₋₆ cycloalkenediyl, —O—, C₁₋₃alkanediyl-O—, —O—C₁₋₇ alkanediyl, C₁₋₃ alkanediyl-O—C₁₋₇ alkanediyl,C₁₋₇ heteroalkanediyl, or —S—C₁₋₇ alkanediyl;

Y is heteroaryl, wherein the heteroaryl is optionally substituted by oneor more of R⁸; or S-heteroaryl, wherein the S-heteroaryl is optionallysubstituted by one or more R¹⁴;

R¹³ is C₁₋₅ alkyl substituted by a bicyclic ring optionally containingat least one heteroatom and a carbonyl group;

R¹⁴ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; and

each R¹⁵ is independently selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, or C₁₋₃alkyl-OR⁸.

In some embodiments, the compound is a compound of Formula (I) orFormula (Ia), wherein:

R¹ is selected from C₃₋₇ alkyl, C₃₋₇ cycloalkyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl;

R² is selected from H, C(O)R¹⁴, C₁₋₇ alkyl, C₃₋₇ cycloalkyl, C₁₋₅alkyl-OR⁸; C₁₋₅ alkyl-NHCOR¹³ wherein R¹³ ispentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3-one; orC₁₋₃ alkyl substituted by aryl, wherein the aryl is optionallysubstituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R³ and R⁷ are H;

R⁴ is selected from C₃₋₇ alkyl, C₃₋₇ cycloalkyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl;

R⁵ is selected from H and C₁₋₇ alkyl;

R⁶ is H;

R⁸ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, and C₃₋₇ cycloalkyl;

X is selected from a bond and C₁₋₇ alkanediyl;

Y is heteroaryl, wherein the heteroaryl is optionally substituted by oneor more of R⁸; or S-heteroaryl, wherein the S-heteroaryl is optionallysubstituted by one or more R¹⁴; and

R¹⁴ is C₁₋₇ alkyl.

In some embodiments, the compound is a compound of Formula (I) orFormula (Ia), wherein:

R¹ is selected from C₃₋₇ alkyl, C₃₋₇ cycloalkyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl;

R² is selected from H, C(O)R¹⁴, C₁₋₇ alkyl, C₃₋₇ cycloalkyl, C₁₋₅alkyl-OR; C₁₋₅ alkyl-NHCOR¹³ wherein R¹³ ispentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3-one; orC₁₋₃ alkyl substituted by aryl, wherein the aryl is optionallysubstituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R³ and R⁷ are H;

R⁴ is selected from C₃₋₇ alkyl, C₃₋₇ cycloalkyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl;

R⁵ is selected from H, C₁₋₇ alkyl, OR⁸, and O—C₁₋₇ alkyl;

R⁶ is H;

R⁸ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, and C₃₋₇ cycloalkyl;

X is selected from a bond, C₁₋₇ alkanediyl, —O—, and —O—C₁₋₇ alkanediyl;

Y is heteroaryl, wherein the heteroaryl is optionally substituted by oneor more of R⁸; or S-heteroaryl, wherein the S-heteroaryl is optionallysubstituted by one or more R¹⁴; and

R¹⁴ is C₁₋₇ alkyl.

In some embodiments, the aryl, the heteroaryl or the S-heteroaryl groupof any of the compounds of the present disclosure are preferablyselected from the group consisting of phenyl, imidazole, pyridine andtriazole, more preferably selected from the group consisting of phenyl,imidazole and pyridine.

In some embodiments, R⁵, X and Y form a spirane or spiro compound at the−4 position of the piperidine ring.

In some embodiments, R⁵, X and Y form a spirane or spiro compound at the−4 position of the piperidine ring and R⁵, X and Y form

wherein

indicates the −4 position of the piperidine ring, the common atom of thespirane

In some embodiments, the compound is of any one of Formulae (VIIIa),(VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VIIIi),(VIIIj), (VIIIk), (VIIIl):

or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomerthereof, wherein Q₁ and Q₂ are each independently O, S, NR⁸, or CR⁸, andR¹, R², R³, R⁴, R⁶, R⁷, R⁸, and Y are as described herein.

In some embodiments, the compound is of Formula (VIIIa) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein Q₁ and Q₂ are each independently O, S, NR⁸, or CR⁸, andR¹, R², R³, R⁴, R⁶, R⁷, R⁸, and Y are as described herein.

In some embodiments, the compound is of Formula (VIIIb) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein Q₁ and Q₂ are each independently O, S, NR⁸, or CR⁸, andR¹, R², R³, R⁴, R⁶, R⁷, R⁸, and Y are as described herein.

In some embodiments, the compound is of Formula (VIIIc) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein Q₁ and Q₂ are each independently O, S, NR⁸, or CR⁸, andR¹, R², R³, R⁴, R⁶, R⁷, R⁸, and Y are as described herein.

In some embodiments, the compound is of Formula (VIIId) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein Q₁ and Q₂ are each independently O, S, NR⁸, or CR⁸, andR¹, R², R³, R⁴, R⁶, R⁷, R⁸, and Y are as described herein.

In some embodiments, the compound is of Formula (VIIIe) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein Q₁ and Q₂ are each independently O, S, NR⁸, or CR⁸, andR¹, R², R³, R⁴, R⁶, R⁷, R⁸, and Y are as described herein.

In some embodiments, the compound is of Formula (VIIIf) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein Q₁ and Q₂ are each independently O, S, NR⁸, or CR⁸, andR¹, R², R³, R⁴, R⁶, R⁷, R⁸, and Y are as described herein.

In some embodiments, the compound is of Formula (VIIIg) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein Q₁ and Q₂ are each independently O, S, NR⁸, or CR⁸, andR¹, R², R³, R⁴, R⁶, R⁷, R⁸, and Y are as described herein.

In some embodiments, the compound is of Formula (VIIIh) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein Q₁ and Q₂ are each independently O, S, NR⁸, or CR⁸, andR¹, R², R³, R⁴, R⁶, R⁷, R⁸, and Y are as described herein.

In some embodiments, the compound is of Formula (VIIIi) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein Q₁ and Q₂ are each independently O, S, NR⁸, or CR⁸, andR¹, R², R³, R⁴, R⁶, R⁷, R⁸, and Y are as described herein.

In some embodiments, the compound is of Formula (VIIIj) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein Q₁ and Q₂ are each independently O, S, NR⁸, or CR⁸, andR¹, R², R³, R⁴, R⁶, R⁷, R⁸, and Y are as described herein.

In some embodiments, the compound is of Formula (VIIIk) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein Q₁ and Q₂ are each independently O, S, NR⁸, or CR⁸, andR¹, R², R³, R⁴, R⁶, R⁷, R⁸, and Y are as described herein.

In some embodiments, the compound is of Formula (VIIIl) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein Q₁ and Q₂ are each independently O, S, NR⁸, or CR⁸, andR¹, R², R³, R⁴, R⁶, R⁷, R⁸, and Y are as described herein.

In some embodiments, the compound is of any one of Formulae (VIIIa1),(VIIIb1), (VIIIc1), (VIIId1), (VIIIe1), (VIIIf1), (VIIIg1), (VIIIh1),(VIIIi1), (VIIIj1), (VIIIk1), (VIIIl1):

or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomerthereof, wherein Q₁ and Q₂ are each independently O, S, NR⁸, or CR⁸, n8ais 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R¹, R², R³, R⁴,R⁶, R⁷, R⁸, and Y are as described herein.

In some embodiments, the compound is of Formula (VIIIa1) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein Q₁ and Q₂ are each independently O, S, NR⁸, or CR⁸, n8ais 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R¹, R², R³, R⁴,R⁶, R⁷, R⁸, and Y are as described herein.

In some embodiments, the compound is of Formula (VIIIb1) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein Q₁ and Q₂ are each independently O, S, NR⁸, or CR⁸, n8ais 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R¹, R², R³, R⁴,R⁶, R⁷, R⁸, and Y are as described herein.

In some embodiments, the compound is of Formula (VIIIc1) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein Q₁ and Q₂ are each independently O, S, NR⁸, or CR⁸, n8ais 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R¹, R², R³, R⁴,R⁶, R⁷, R⁸, and Y are as described herein.

In some embodiments, the compound is of Formula (VIIId1) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein Q₁ and Q₂ are each independently O, S, NR⁸, or CR⁸, n8ais 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R¹, R², R³, R⁴,R⁶, R⁷, R⁸, and Y are as described herein.

In some embodiments, the compound is of Formula (VIIIe1) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein Q₁ and Q₂ are each independently O, S, NR⁸, or CR⁸, n8ais 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R¹, R², R³, R⁴,R⁶, R⁷, R⁸, and Y are as described herein.

In some embodiments, the compound is of Formula (VIIIf1) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein Q₁ and Q₂ are each independently O, S, NR⁸, or CR⁸, n8ais 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R¹, R², R³, R⁴,R⁶, R⁷, R⁸, and Y are as described herein.

In some embodiments, the compound is of Formula (VIIIg1) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein Q₁ and Q₂ are each independently O, S, NR⁸, or CR⁸, n8ais 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R¹, R², R³, R⁴,R⁶, R⁷, R⁸, and Y are as described herein.

In some embodiments, the compound is of Formula (VIIIh1) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein Q₁ and Q₂ are each independently O, S, NR⁸, or CR⁸, n8ais 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R¹, R², R³, R⁴,R⁶, R⁷, R⁸, and Y are as described herein.

In some embodiments, the compound is of Formula (VIIIi1) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein Q₁ and Q₂ are each independently O, S, NR⁸, or CR⁸, n8ais 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R¹, R², R³, R⁴,R⁶, R⁷, R⁸, and Y are as described herein.

In some embodiments, the compound is of Formula (VIIIj1) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein Q₁ and Q₂ are each independently O, S, NR⁸, or CR⁸, n8ais 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R¹, R², R³, R⁴,R⁶, R⁷, R⁸, and Y are as described herein.

In some embodiments, the compound is of Formula (VIIIk1) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein Q₁ and Q₂ are each independently O, S, NR⁸, or CR⁸, n8ais 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R¹, R², R³, R⁴,R⁶, R⁷, R⁸, and Y are as described herein.

In some embodiments, the compound is of Formula (VIIIl1) or apharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein Q₁ and Q₂ are each independently O, S, NR⁸, or CR⁸, n8ais 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R¹, R², R³, R⁴,R⁶, R⁷, R⁸, and Y are as described herein.

In some embodiments, Y is NR¹⁰R¹², wherein R¹⁰ and R¹² can form a ringwherein the ring contains the N of NR¹⁰R¹² and optionally one furtherheteroatom selected from O and N, wherein if the one further heteroatomis N, it is optionally substituted by R⁸.

In some embodiments, the compound is of any one of Formulae (IXa),(IXb), (IXc), or (IXd):

or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomerthereof, wherein n10 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or3, and R¹, R², R³, R⁴, R⁶, R⁷, R¹⁰, R¹² and Y are as described herein.

In some embodiments, the compound is of Formula (IXa) or apharmaceutically acceptable salt, hydrate, solvate, or stereoisomerthereof, wherein n10 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or3, and R¹, R², R³, R⁴, R⁶, R⁷, R¹⁰, R¹² and Y are as described herein.

In some embodiments, the compound is of Formula (IXb) or apharmaceutically acceptable salt, hydrate, solvate, or stereoisomerthereof, wherein n10 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or3, and R¹, R², R³, R⁴, R⁶, R⁷, R¹⁰, R¹² and Y are as described herein.

In some embodiments, the compound is of Formula (IXc) or apharmaceutically acceptable salt, hydrate, solvate, or stereoisomerthereof, wherein n10 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or3, and R¹, R², R³, R⁴, R⁶, R⁷, R¹⁰, R¹² and Y are as described herein.

In some embodiments, the compound is of Formula (IXd) or apharmaceutically acceptable salt, hydrate, solvate, or stereoisomerthereof, wherein n10 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or3, and R¹, R², R³, R⁴, R⁶, R⁷, R¹⁰, R¹² and Y are as described herein.

In some embodiments, the compound is of any one of Formulae (IXa1),(IXb1), (IXc1), or (IXd1):

or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomerthereof, wherein n10 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or3, R¹, R², R³, R⁴, R⁶, R⁷, R¹⁰, R¹² and Y are as described herein, and *indicates the Z-isomer of the spiro compound.

In some embodiments, the compound is of Formula (IXa1) or apharmaceutically acceptable salt, hydrate, solvate, or stereoisomerthereof, wherein n10 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or3, R¹, R², R³, R⁴, R⁶, R⁷, R¹⁰, R¹² and Y are as described herein, and *indicates the Z-isomer of the spiro compound.

In some embodiments, the compound is of Formula (IXb1) or apharmaceutically acceptable salt, hydrate, solvate, or stereoisomerthereof, wherein n10 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or3, R¹, R², R³, R⁴, R⁶, R⁷, R¹⁰, R¹² and Y are as described herein, and *indicates the Z-isomer of the spiro compound.

In some embodiments, the compound is of Formula (IXc1) or apharmaceutically acceptable salt, hydrate, solvate, or stereoisomerthereof, wherein n10 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or3, R¹, R², R³, R⁴, R⁶, R⁷, R¹⁰, R¹² and Y are as described herein, and *indicates the Z-isomer of the spiro compound.

In some embodiments, the compound is of Formula (IXd1) or apharmaceutically acceptable salt, hydrate, solvate, or stereoisomerthereof, wherein n10 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or3, R¹, R², R³, R⁴, R⁶, R⁷, R¹⁰, R¹² and Y are as described herein, and *indicates the Z-isomer of the spiro compound.

In some embodiments, the compound is a compound of Formula (I) orFormula (Ia), wherein:

R¹ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R² is selected from H, C(O)R¹⁴, C(O)NR¹⁵R¹⁵, C(O)OR, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₅alkyl-OR⁸, C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₅alkyl-NHCOR¹³, or C₁₋₃ alkyl substituted by aryl or heteroaryl, whereinthe aryl or the heteroaryl is optionally substituted by halogen, C₁₋₄alkyl or C₃₋₅ cycloalkyl; with the proviso that when R² is C(O)NR¹⁵R¹⁵,both R¹⁵ can form a ring wherein the ring contains the N of NR¹⁵R¹⁵ andoptionally one further heteroatom selected from O and N, wherein if theone further heteroatom is N, it is optionally substituted by R⁸;

R³ and R⁷ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, alloptionally substituted by halogen, OR⁸, NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁴ is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁵ is selected from C₁₋₇ alkyl, OR⁸, or SR⁸; wherein C₁₋₇ alkyl, OR⁸ orSR⁸ of R⁵ can form a ring with any part of X;

R⁶ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, all optionally substituted by halogen,OR⁸, NR⁸R¹¹; C₁₋₃ alkyl substituted by C(O)NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; or isimidazolidinone;

R⁸ and R¹¹ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl;

X is selected from —O—C₁₋₇ alkanediyl, —S—C₁₋₇ alkanediyl, or C₁₋₇alkanediyl, and wherein —O—C₁₋₇ alkanediyl, —S—C₁₋₇ alkanediyl or C₁₋₇alkanediyl of X can form a ring with any part of R⁵;

Y is NR¹⁰R¹², wherein R¹⁰ and R¹² can form a ring wherein the ringcontains the N of NR¹⁰R¹² and optionally one further heteroatom selectedfrom O and N, wherein if the one further heteroatom is N, it isoptionally substituted by R⁸;

R¹³ is C₁₋₅ alkyl substituted by a bicyclic ring optionally containingat least one heteroatom and a carbonyl group;

R¹⁴ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; and

each R¹⁵ is independently selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, or C₁₋₃alkyl-OR⁸.

In some embodiments, the compound is a compound of Formula (I) orFormula (Ia), wherein:

R¹ is selected from C₃₋₇ alkyl, C₃₋₇ cycloalkyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl;

R² is selected from H, C(O)R¹⁴, C₁₋₇ alkyl, C₃₋₇ cycloalkyl, C₁₋₅alkyl-OR⁸; C₁₋₅ alkyl-NHCOR¹³ wherein R¹³ ispentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3-one; orC₁₋₃ alkyl substituted by aryl, wherein the aryl is optionallysubstituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R³ and R⁷ are H;

R⁴ is selected from C₃₋₇ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkyl substitutedby aryl or heteroaryl;

R⁵ is OR⁸, and OR⁸ of R⁵ can form a ring with any part of X;

R⁶ is H;

R⁸ and R¹¹ are C₁₋₇ alkyl;

X is —O—C₁₋₇ alkanediyl and wherein —O—C₁₋₇ alkanediyl of X can form aring with any part of R⁵; and

Y is NR¹⁰R¹², wherein R¹⁰ and R¹² can form a ring wherein the ringcontains the N of NR¹⁰R¹² and optionally one further heteroatom selectedfrom O and N, wherein if the one further heteroatom is N, it isoptionally substituted by R⁸.

Some preferred embodiments of the present application relate to thecompounds having one of the following structures or being one of thefollowing compounds, pharmaceutically-acceptable salts, hydrates,solvates, or stereoisomers thereof:

Some preferred embodiments of the present application relate to thecompounds having one of the following structures or being one of thefollowing compounds, pharmaceutically-acceptable salts, hydrates,solvates, or stereoisomers thereof:

Some embodiments of the present application relate to the compoundshaving one of the following structures or being one of the followingcompounds, pharmaceutically-acceptable salts, hydrates, solvates, orstereoisomers thereof:

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts of the compounds formed by the process of the presentapplication which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theapplication, or separately by reacting the free base or acid functionwith a suitable acid or base.

Examples of pharmaceutically acceptable salts include, but are notlimited to, nontoxic acid addition salts: salts formed with inorganicacids such as hydrochloric acid, hydrobromic acid, phosphoric acid,sulfuric acid and perchloric acid, or with organic acids such as aceticacid, maleic acid, tartaric acid, citric acid, succinic acid or malonicacid. Other pharmaceutically acceptable salts include, but are notlimited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,citrate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate,gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Representative alkali or alkaline earth metal salts includesodium, lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters of the compounds formed by the process of the present applicationwhich hydrolyze in vivo and include those that break down readily in thehuman body to leave the parent compound or a salt thereof. Suitableester groups include, for example, those derived from pharmaceuticallyacceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic,cycloalkanoic and alkanedioic acids, in which each alkyl or alkenylmoiety advantageously has not more than 6 carbon atoms. Examples ofparticular esters include, but are not limited to, formates, acetates,propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein, refersto those prodrugs of the compounds formed by the process of the presentapplication which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswith undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the present application. “Prodrug”, as used herein,means a compound which is convertible in vivo by metabolic means (e.g.,by hydrolysis) to afford any compound delineated by the formulae of theinstant application. Various forms of prodrugs are known in the art, forexample, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier(1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, AcademicPress (1985); Krogsgaard-Larsen, et al., (ed). “Design and Applicationof Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191(1991); Bundgaard, et al., Journal of Drug Deliver Reviews,8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq.(1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug DeliverySystems, American Chemical Society (1975); and Bernard Testa & JoachimMayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry,Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

This application also encompasses pharmaceutical compositionscontaining, and methods of treating disorders through administering,pharmaceutically acceptable prodrugs of compounds of the application.For example, compounds of the application having free amino, amido,hydroxy or carboxylic groups can be converted into prodrugs. Prodrugsinclude compounds wherein an amino acid residue, or a polypeptide chainof two or more (e.g., two, three or four) amino acid residues iscovalently joined through an amide or ester bond to a free amino,hydroxy or carboxylic acid group of compounds of the application. Theamino acid residues include but are not limited to the 20 naturallyoccurring amino acids commonly designated by three letter symbols andalso includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methionine sulfone.Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. Freehydroxy groups may be derivatized using groups including but not limitedto hemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxy carbonyls, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem. 1996,39, 10. Free amines can also be derivatized as amides, sulfonamides orphosphonamides. All of these prodrug moieties may incorporate groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities.

The application also provides for a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of theapplication, or an enantiomer, diastereomer, stereoisomer, orpharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

In another aspect, the application provides a method of synthesizing acompound disclosed herein.

The synthesis of the compounds of the application can be found hereinand in the Examples below.

Other embodiments are a method of making a compound of any of theformulae herein using any one, or combination of, reactions delineatedherein. The method can include the use of one or more intermediates orchemical reagents delineated herein.

Another aspect is an isotopically labeled compound of any of theformulae delineated herein. Such compounds have one or more isotopeatoms which may or may not be radioactive (e.g., ³H, ²H, ¹⁴C, ¹³C, ¹⁸F,³⁵S, ³²P, ¹²⁵I, and ¹³¹I) introduced into the compound. Such compoundsare useful for drug metabolism studies and diagnostics, as well astherapeutic applications.

A compound of the application can be prepared as a pharmaceuticallyacceptable acid addition salt by reacting the free base form of thecompound with a pharmaceutically acceptable inorganic or organic acid.Alternatively, a pharmaceutically acceptable base addition salt of acompound of the application can be prepared by reacting the free acidform of the compound with a pharmaceutically acceptable inorganic ororganic base.

Alternatively, the salt forms of the compounds of the application can beprepared using salts of the starting materials or intermediates.

The free acid or free base forms of the compounds of the application canbe prepared from the corresponding base addition salt or acid additionsalt from, respectively. For example, a compound of the application inan acid addition salt form can be converted to the corresponding freebase by treating with a suitable base (e.g., ammonium hydroxidesolution, sodium hydroxide, and the like). A compound of the applicationin a base addition salt form can be converted to the corresponding freeacid by treating with a suitable acid (e.g., hydrochloric acid, etc.).

The compounds of the present invention may be used in the form ofpharmaceutically-acceptable salts derived from inorganic or organicacids. By “pharmaceutically-acceptable salt” is meant those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio.Pharmaceutically-acceptable salts are well-known in the art. The saltsmay be prepared in situ during the final isolation and purification ofthe compounds of the invention or separately by reacting a free basefunction with a suitable acid.

Representative acid addition salts include, but are not limited totrifluoroacetic acid (TFA), formate, acetate, adipate, alginate,citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,camphorate, camphorsulfonate, digluconate, glycerophosphate,hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate),lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate,oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate,pivalate, propionate, succinate, tartrate, thiocyanate, phosphate,glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, thebasic nitrogen-containing groups can be quaternized with such agents aslower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyland diamyl sulfates; long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides; arylalkyl halides likebenzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which maybe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,sulphuric acid and phosphoric acid and such organic acids as oxalicacid, maleic acid, succinic acid and citric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as the hydroxide,carbonate or bicarbonate of a pharmaceutically acceptable metal cationor with ammonia or an organic primary, secondary or tertiary amine.Pharmaceutically-acceptable basic addition salts include, but are notlimited to, cations based on alkali metals or alkaline earth metals suchas lithium, sodium, potassium, calcium, magnesium and aluminum salts andthe like and nontoxic quaternary ammonia and amine cations includingammonium, tetramethylammonium, tetraethylammonium, methylamine,dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamineand the like. Other representative organic amines useful for theformation of base addition salts include ethylenediamine, ethanolamine,diethanolamine, piperidine, piperazine and the like.

Prodrugs of the compounds of the application can be prepared by methodsknown to those of ordinary skill in the art (e.g., for further detailssee Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters,Vol. 4, p. 1985). For example, appropriate prodrugs can be prepared byreacting a non-derivatized compound of the application with a suitablecarbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate,para-nitrophenyl carbonate, or the like).

Protected derivatives of the compounds of the application can be made bymeans known to those of ordinary skill in the art. A detaileddescription of techniques applicable to the creation of protectinggroups and their removal include, but are not limited to, thoseillustrated in T. W. Greene, “Protecting Groups in Organic Chemistry”,3rd edition, John Wiley and Sons, Inc., 1999.

Compounds of the present application can be conveniently prepared orformed during the process of the application, as solvates (e.g.,hydrates). Hydrates of compounds of the present application can beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

Acids and bases useful in the methods herein are known in the art. Acidcatalysts are any acidic chemical, which can be inorganic (e.g.,hydrochloric, sulfuric, nitric acids, aluminum trichloride) or organic(e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid,ytterbium triflate) in nature. Acids are useful in either catalytic orstoichiometric amounts to facilitate chemical reactions. Bases are anybasic chemical, which can be inorganic (e.g., sodium bicarbonate,potassium hydroxide) or organic (e.g., triethylamine, pyridine) innature. Bases are useful in either catalytic or stoichiometric amountsto facilitate chemical reactions.

Combinations of substituents and variables envisioned by thisapplication are only those that result in the formation of stablecompounds. The term “stable”, as used herein, refers to compounds whichpossess stability sufficient to allow manufacture and which maintainsthe integrity of the compound for a sufficient period of time to beuseful for the purposes detailed herein (e.g., therapeutic orprophylactic administration to a subject).

When any variable (e.g., R¹⁴) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with one or more R¹⁴moieties, then R¹⁴ at each occurrence is selected independently from thedefinition of R¹⁴. Also, combinations of substituents and/or variablesare permissible, but only if such combinations result in stablecompounds within a designated atom's normal valency.

In addition, some of the compounds of this application have one or moredouble bonds, or one or more asymmetric centers. Such compounds canoccur as racemates, racemic mixtures, single enantiomers, individualdiastereomers, diastereomeric mixtures, and cis- or trans- or E- orZ-double isomeric forms, and other stereoisomeric forms that may bedefined, in terms of absolute stereochemistry, as (R)- or (S)-, or as(D)- or (L)- for amino acids. When the compounds described hereincontain olefinic double bonds or other centers of geometric asymmetry oreven E or Z isomerism across several bonds and/or rings, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers. The configuration of any carbon-carbon doublebond appearing herein is selected for convenience only and is notintended to designate a particular configuration unless the text sostates; thus a carbon-carbon double bond depicted arbitrarily herein astrans may be cis, trans, or a mixture of the two in any proportion. Allsuch isomeric forms of such compounds are expressly included in thepresent application.

Optical isomers may be prepared from their respective optically activeprecursors by the procedures described herein, or by resolving theracemic mixtures. The resolution can be carried out in the presence of aresolving agent, by chromatography or by repeated crystallization or bysome combination of these techniques which are known to those skilled inthe art. Further details regarding resolutions can be found in Jacques,et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons,1981).

“Isomerism” means compounds that have identical molecular formulae butdiffer in the sequence of bonding of their atoms or in the arrangementof their atoms in space. Isomers that differ in the arrangement of theiratoms in space are termed “stereoisomers”. Stereoisomers that are notmirror images of one another are termed “diastereoisomers”, andstereoisomers that are non-superimposable mirror images of each otherare termed “enantiomers” or sometimes optical isomers. A mixturecontaining equal amounts of individual enantiomeric forms of oppositechirality is termed a “racemic mixture”.

A carbon atom bonded to four non-identical substituents is termed a“chiral center”.

“Chiral isomer” means a compound with at least one chiral center.Compounds with more than one chiral center may exist either as anindividual diastereomer or as a mixture of diastereomers, termed“diastereomeric mixture”. When one chiral center is present, astereoisomer may be characterized by the absolute configuration (R or S)of that chiral center. Absolute configuration refers to the arrangementin space of the substituents attached to the chiral center. Thesubstituents attached to the chiral center under consideration areranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog.(Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahnet al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951(London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem.Educ. 1964, 41, 116).

“Geometric isomer” means the diastereomers that owe their existence tohindered rotation about double bonds and/or other rigid structures suchas a ring or polycyclic system. These configurations are differentiatedin their names by the prefixes cis and trans, or Z and E, which indicatethat the groups are on the same or opposite side of the double bondand/or other rigid structures such as a ring or a polycyclic system inthe molecule according to the Cahn-Ingold-Prelog rules.

Furthermore, the structures and other compounds discussed in thisapplication include all atropic isomers thereof. “Atropic isomers” are atype of stereoisomer in which the atoms of two isomers are arrangeddifferently in space. Atropic isomers owe their existence to arestricted rotation caused by hindrance of rotation of large groupsabout a central bond. Such atropic isomers typically exist as a mixture,however as a result of recent advances in chromatography techniques; ithas been possible to separate mixtures of two atropic isomers in selectcases.

“Tautomer” is one of two or more structural isomers that exist inequilibrium and is readily converted from one isomeric form to another.This conversion results in the formal migration of a hydrogen atomaccompanied by a switch of adjacent conjugated double bonds. Tautomersexist as a mixture of a tautomeric set in solution. In solid form,usually one tautomer predominates. In solutions where tautomerization ispossible, a chemical equilibrium of the tautomers will be reached. Theexact ratio of the tautomers depends on several factors, includingtemperature, solvent and pH. The concept of tautomers that areinterconvertable by tautomerizations is called tautomerism.

Of the various types of tautomerism that are possible, two are commonlyobserved. In keto-enol tautomerism a simultaneous shift of electrons anda hydrogen atom occurs. Ring-chain tautomerism arises as a result of thealdehyde group (—CHO) in a sugar chain molecule reacting with one of thehydroxy groups (—OH) in the same molecule to give it a cyclic(ring-shaped) form as exhibited by glucose. Common tautomeric pairs are:ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomerismin heterocyclic rings (e.g., in nucleobases such as guanine, thymine andcytosine), amine-enamine and enamine-enamine. The compounds of thisapplication may also be represented in multiple tautomeric forms, insuch instances, the application expressly includes all tautomeric formsof the compounds described herein (e.g., alkylation of a ring system mayresult in alkylation at multiple sites, the application expresslyincludes all such reaction products).

In the present application, the structural formula of the compoundrepresents a certain isomer for convenience in some cases, but thepresent application includes all isomers, such as geometrical isomers,optical isomers based on an asymmetrical carbon, stereoisomers,tautomers, and the like. In the present specification, the structuralformula of the compound represents a certain isomer for convenience insome cases, but the present application includes all isomers, such asgeometrical isomers, optical isomers based on an asymmetrical carbon,stereoisomers, tautomers, and the like.

Compounds of the present invention can exist as stereoisomers whereinasymmetric or chiral centers are present. These compounds are designatedby the symbols “R” or “S”, depending on the configuration ofsubstituents around the chiral carbon atom. The present inventioncontemplates various stereoisomers and mixtures thereof. Stereoisomersinclude enantiomers and diastereomers, and mixtures of enantiomers ordiastereomers. Individual stereoisomers of compounds of the presentinvention can be prepared synthetically from commercially availablestarting materials which contain asymmetric or chiral centers or bypreparation of racemic mixtures followed by resolution well-known tothose of ordinary skill in the art. These methods of resolution areexemplified by (1) attachment of a mixture of enantiomers to a chiralauxiliary, separation of the resulting mixture of diastereomers byrecrystallization or chromatography and liberation of the optically pureproduct from the auxiliary, (2) salt formation employing an opticallyactive resolving agent, or (3) direct separation of the mixture ofoptical enantiomers on chiral chromatographic columns.

Geometric isomers can also exist in the compounds of the presentinvention. The present invention contemplates the various geometricisomers and mixtures thereof resulting from the arrangement ofsubstituents around a carbon-carbon double bond or arrangement ofsubstituents around a carbocyclic or heterocyclic ring.

Compounds of the present invention can also exist as racemates which isgiven the descriptor “rac”. The term racemate, as used herein, means anequimolar mixture of a pair of enantiomers. A racemate is usually formedwhen synthesis results in the generation of a stereocenter. As usedherein, the term racemic mixture means racemate. Compounds of thepresent invention can also exist as diastereomeric meso forms which isgiven the descriptor “rel”. The term diastereomeric meso form as usedherein means achiral forms with a pseudostereogenic C-atom, which isgiven the descriptor “r” or “s”, respectively.

Additionally, the compounds of the present application, for example, thesalts of the compounds, can exist in either hydrated or unhydrated (theanhydrous) form or as solvates with other solvent molecules.Non-limiting examples of hydrates include monohydrates, dihydrates, etc.Non-limiting examples of solvates include ethanol solvates, acetonesolvates, etc.

“Solvate” means solvent addition forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate; and if the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one molecule of the substance inwhich the water retains its molecular state as H₂O.

It should be appreciated that solvates and hydrates of the compoundaccording to formula (I) or formula (Ia) are also within the scope ofthe present application. Methods of solvation are generally known in theart.

A further embodiment of the present invention may also include compoundswhich are identical to the compounds of formula (I) or formula (Ia)except that one or more atoms are replaced by an atom having an atomicmass number or mass different from the atomic mass number or massusually found in nature, e.g. compounds enriched in ²H (D), ³H, ¹³C,¹²⁷I, etc. These isotopic analogs and their pharmaceutical salts andformulations are considered useful agents in therapy and/or diagnosis,for example, but not limited to, where a fine-tuning of in vivohalf-life time could lead to an optimized dosage regimen.

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the formulae herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. In addition, the solvents, temperatures, reaction durations,etc. delineated herein are for purposes of illustration only and one ofordinary skill in the art will recognize that variation of the reactionconditions can produce the desired bridged macrocyclic products of thepresent application. Synthetic chemistry transformations and protectinggroup methodologies (protection and deprotection) useful in synthesizingthe compounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The compounds of this application may be modified by appending variousfunctionalities via any synthetic means delineated herein to enhanceselective biological properties. Such modifications are known in the artand include those which increase biological penetration into a givenbiological system (e.g., blood, lymphatic system, central nervoussystem), increase oral availability, increase solubility to allowadministration by injection, alter metabolism and alter rate ofexcretion.

The compounds of the application are defined herein by their chemicalstructures and/or chemical names. Where a compound is referred to byboth a chemical structure and a chemical name, and the chemicalstructure and chemical name conflict, the chemical structure isdeterminative of the compound's identity.

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof.

Methods of Synthesizing the Compounds

The compounds of the invention may be prepared by the exemplaryprocesses described in the following reaction schemes or by theprocesses described in the examples below. Exemplary reagents andprocedures for these reactions appear hereinafter. Starting materialscan be purchased or readily prepared by one of ordinary skill in theart.

Compounds of the present application can be prepared in a variety ofways using commercially available starting materials, compounds known inthe literature, or from readily prepared intermediates, by employingstandard synthetic methods and procedures either known to those skilledin the art, or which will be apparent to the skilled artisan in light ofthe teachings herein. Standard synthetic methods and procedures for thepreparation of organic molecules and functional group transformationsand manipulations can be obtained from the relevant scientificliterature or from standard textbooks in the field. Although not limitedto any one or several sources, classic texts such as Smith, M. B.,March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms,and Structure, 5^(th) edition, John Wiley & Sons: New York, 2001; andGreene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis,3^(rd) edition, John Wiley & Sons: New York, 1999, incorporated byreference herein, are useful and recognized reference textbooks oforganic synthesis known to those in the art. The following descriptionsof synthetic methods are designed to illustrate, but not to limit,general procedures for the preparation of compounds of the presentapplication. The processes generally provide the desired final compoundat or near the end of the overall process, although it may be desirablein certain instances to further convert the compound to apharmaceutically acceptable salt, ester or prodrug thereof. Suitablesynthetic routes are depicted in the schemes below.

Those skilled in the art will recognize if a stereocenter exists in thecompounds disclosed herein. Accordingly, the present applicationincludes both possible stereoisomers (unless specified in the synthesis)and includes not only racemic compounds but the individual enantiomersand/or diastereomers as well. When a compound is desired as a singleenantiomer or diastereomer, it may be obtained by stereospecificsynthesis or by resolution of the final product or any convenientintermediate. Resolution of the final product, an intermediate, or astarting material may be affected by any suitable method known in theart. See, for example, “Stereochemistry of Organic Compounds” by E. L.Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

The compounds of the present application can be prepared in a number ofways well known to those skilled in the art of organic synthesis. By wayof example, compounds of the present application can be synthesizedusing the methods described below, together with synthetic methods knownin the art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. Preferred methods include butare not limited to those methods described below.

Compounds of the present application can be synthesized by following thesteps outlined in General Scheme 1 (Method A), General Scheme 2 (MethodB1 and Method B2) and General Scheme 3 (Method C) which comprisedifferent sequences of assembling intermediates. Starting materials areeither commercially available or made by known procedures in thereported literature or as illustrated.

Method A: Using I where P is a suitable protecting group such as tBoc ornosyl, I and II are coupled using a dehydrating agent such as DCC orHATU in a suitable solvent such as DMF or NMP. The compounds where R² isH are obtained by deprotection under standard conditions. The compoundswhere is R² is C(O)R¹⁴, C(O)NR¹⁵R¹⁵or C(O)OR⁵ are obtained by acylationof the secondary amine. The compounds where is R² not the above areobtained by reductive amination of the secondary amine with theappropriate aldehyde or ketone.

Method B1: Using the appropriate precursor IIIa and IIIb, III isprepared by amide coupling using a dehydrating agent such as DCC or HATUin a suitable solvent such as DMF or NMP.

Method B2: Z can be elaborated into the desired functional group usingreaction sequences described in Table X. In cases where compound of theinvention has R²═H, the starting material of Method B will have P as aprotecting group, such as t-Boc or Nosyl. The compounds of the inventionare then obtained by deprotection under standard conditions. Thecompounds where is R² is C(O)R¹⁴, C(O)NR¹⁵R¹⁵or C(O)OR¹⁵ are obtained byacylation of the secondary amine at this point. The compounds where isR² is not the above are obtained by reductive amination of the secondaryamine with the appropriate aldehyde or ketone.

Method C: I may be prepared following the sequence described in MethodC. Using the appropriate Ia bearing a protecting group P and Ib bearinga short alkyl group R, the coupling is performed by using a dehydratingagent such as DCC or HATU in a suitable solvent such as DMF or NMP. Theresulting dipeptide ester is reacted with Ic. When P2 is Br, Ic isreacted in a suitable solvent such as DMF or DMSO in the presence of abase such as potassium carbonate or cesium carbonate to yield ashort-chain ester derivative of I. When P2 is a protected alcohol suchas OTHP or OTBDMS, the short chain ester of I is obtained by firstreacting Ic with the dipeptide ester in a suitable solvent such as DMFor DMSO in the presence of a base such as potassium carbonate or cesiumcarbonate, followed by alcohol deprotection, followed by alcoholactivation and coupling using methods like the Mitsunobu reaction or theformation of a mesylate and base-catalyzed cyclization. I is finallyobtained by hydrolysis using a base such as sodium hydroxide orpotassium carbonate, in a suitable solvent such as water or a water-THFmixture.

Pharmaceutical Compositions

In a further aspect the present invention provides a pharmaceuticalcomposition comprising a compound of formula (I) or formula (Ia)according to the invention and a pharmaceutically acceptable diluent,excipient or carrier.

In one embodiment the pharmaceutical composition further comprisesanother pharmaceutical active agent.

In one embodiment, the invention provides a pharmaceutical compositioncomprising a compound of formula (I) or formula (Ia) according to theinvention and a pharmaceutically acceptable diluent, excipient orcarrier, wherein said compound of formula (I) or formula (Ia) is presentin a therapeutically effective amount.

The expression “effective amount” or “therapeutically effective amount”as used herein refers to an amount capable of invoking one or more ofthe following effects in a subject receiving the combination of thepresent invention: (i) inhibition or arrest of tumor growth, including,reducing the rate of tumor growth or causing complete growth arrest;(ii) reduction in the number of tumor cells; (iii) reduction in tumorsize; (iv) reduction in tumor number; (v) inhibition of metastasis(i.e., reduction, slowing down or complete stopping) of tumor cellinfiltration into peripheral organs; (vi) enhancement of antitumorimmune response, which may, but does not have to, result in theregression or elimination of the tumor; (vii) relief, to some extent, ofone or more symptoms associated with cancer; (viii) increase inprogression-free survival (PFS) and/or; overall survival (OS) of thesubject receiving the combination.

The compounds of the present invention may, in accordance with theinvention, be administered in single or divided doses by oral,parenteral, inhalatory, rectal or topical administration includingcutaneous, ophthalmic, mucosal scalp, sublingual, buccal and intranasalroutes of administration; further, the compounds provided by theinvention may be formulated to be used for the treatment of leukocytepopulations in vivo, ex vivo and in vitro.

When the compounds of the present invention are to be administered e.g.by the oral route, they may be administered as medicaments in the formof pharmaceutical compositions which contain them in association with apharmaceutically acceptable diluent, excipient or carrier material. Thusthe present invention also provides a pharmaceutical compositioncomprising the compounds according to the invention as described supraand one or more pharmaceutically acceptable diluent, excipient orcarrier. The pharmaceutical compositions can be prepared in aconventional manner and finished dosage forms can be solid dosage forms,for example, tablets, dragees, capsules, and the like, or liquid dosageforms, for example solutions, suspensions, emulsions and the like.Pharmaceutically acceptable diluent, excipient or carrier includesterile aqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersion. The use of such media and agents for pharmaceutically activesubstances is known in the art.

In one embodiment, the invention provides a pharmaceutical compositioncomprising a compound of formula (I) or formula (Ia) according to theinvention and at least one pharmaceutically acceptable diluent,excipient or carrier, wherein the composition is a tablet or a capsule,preferably a tablet.

The amount of the compounds of the invention to be administered willvary depending upon factors such as the particular compound, diseasecondition and its severity, according to the particular circumstancessurrounding the case, including, e.g., the specific compound beingadministered, the route of administration, the condition being treated,the target area being treated, and the subject or host being treated

In another aspect, the application provides a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of thepresent application or an enantiomer, diastereomer, or stereoisomerthereof, or pharmaceutically acceptable salt, hydrate, solvate, orprodrug thereof, and a pharmaceutically acceptable carrier.

Compounds of the application can be administered as pharmaceuticalcompositions by any conventional route, in particular enterally, e.g.,orally, e.g., in the form of tablets or capsules, or parenterally, e.g.,in the form of injectable solutions or suspensions, or topically, e.g.,in the form of lotions, gels, ointments or creams, or in a nasal orsuppository form. Pharmaceutical compositions comprising a compound ofthe present application in free form or in a pharmaceutically acceptablesalt form in association with at least one pharmaceutically acceptablecarrier or diluent can be manufactured in a conventional manner bymixing, granulating or coating methods. For example, oral compositionscan be tablets or gelatin capsules comprising the active ingredienttogether with a) diluents, e.g., lactose, dextrose, sucrose, mannitol,sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum,stearic acid, its magnesium or calcium salt and/or polyethyleneglycol;for tablets also c) binders, e.g., magnesium aluminum silicate, starchpaste, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose and or polyvinylpyrrolidone; if desired d)disintegrants, e.g., starches, agar, alginic acid or its sodium salt, oreffervescent mixtures; and/or e) absorbents, colorants, flavors andsweeteners. Injectable compositions can be aqueous isotonic solutions orsuspensions, and suppositories can be prepared from fatty emulsions orsuspensions. The compositions may be sterilized and/or containadjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressureand/or buffers. In addition, they may also contain other therapeuticallyvaluable substances. Suitable formulations for transdermal applicationsinclude an effective amount of a compound of the present applicationwith a carrier. A carrier can include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host. Forexample, transdermal devices are in the form of a bandage comprising abacking member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundto the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.Matrix transdermal formulations may also be used. Suitable formulationsfor topical application, e.g., to the skin and eyes, are preferablyaqueous solutions, ointments, creams or gels well-known in the art. Suchmay contain solubilizers, stabilizers, tonicity enhancing agents,buffers and preservatives.

The pharmaceutical compositions of the present application comprise atherapeutically effective amount of a compound of the presentapplication formulated together with one or more pharmaceuticallyacceptable carriers. As used herein, the term “pharmaceuticallyacceptable carrier” means a non-toxic, inert solid, semi-solid or liquidfiller, diluent, encapsulating material or formulation auxiliary of anytype. Some examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, ion exchangers,alumina, aluminum stearate, lecithin, serum proteins, such as humanserum albumin, buffer substances such as phosphates, glycine, sorbicacid, or potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, polyacrylates, waxes, polyethylenepolyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose andsucrose; starches such as corn starch and potato starch; cellulose andits derivatives such as sodium carboxymethyl cellulose, ethyl celluloseand cellulose acetate; powdered tragacanth; malt; gelatin; talc;excipients such as cocoa butter and suppository waxes, oils such aspeanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; cornoil and soybean oil; glycols such a propylene glycol or polyethyleneglycol; esters such as ethyl oleate and ethyl laurate, agar; bufferingagents such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water, isotonic saline; Ringer's solution; ethyl alcohol,and phosphate buffer solutions, as well as other non-toxic compatiblelubricants such as sodium lauryl sulfate and magnesium stearate, as wellas coloring agents, releasing agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can alsobe present in the composition, according to the judgment of theformulator.

The pharmaceutical compositions of this application can be administeredto humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), buccally, or as an oral or nasal spray.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan, andmixtures thereof. Besides inert diluents, the oral compositions can alsoinclude adjuvants such as wetting agents, emulsifying and suspendingagents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous, oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisapplication with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid compositions of a similar type may also be employed as fillers insoft and hard filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents.

Dosage forms for topical or transdermal administration of a compound ofthis application include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this application.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this application, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisapplication, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

Compounds and compositions of the application can be administered intherapeutically effective amounts in a combinational therapy with one ormore therapeutic agents (pharmaceutical combinations) or modalities,e.g., an anti-proliferative, anti-cancer, immunomodulatory oranti-inflammatory agent. Where the compounds of the application areadministered in conjunction with other therapies, dosages of theco-administered compounds will of course vary depending on the type ofco-drug employed, on the specific drug employed, on the condition beingtreated and so forth. Compounds and compositions of the application canbe administered in therapeutically effective amounts in a combinationaltherapy with one or more therapeutic agents (pharmaceuticalcombinations) or modalities, e.g., anti-proliferative, anti-cancer,immunomodulatory or anti-inflammatory agent, and/or non-drug therapies,etc. For example, synergistic effects can occur with anti-proliferative,anti-cancer, immunomodulatory or anti-inflammatory substances. Where thecompounds of the application are administered in conjunction with othertherapies, dosages of the co-administered compounds will of course varydepending on the type of co-drug employed, on the specific drugemployed, on the condition being treated and so forth.

Combination therapy includes the administration of the subject compoundsin further combination with one or more other biologically activeingredients. For instance, the compounds of the application can be usedin combination with other pharmaceutically active compounds, preferablycompounds that are able to enhance the effect of the compounds of theapplication. The compounds of the application can be administeredsimultaneously (as a single preparation or separate preparation), intemporal proximity, or sequentially to the other drug therapy ortreatment modality. In general, a combination therapy envisionsadministration of two or more drugs during a single cycle or course oftherapy.

In another aspect of the application, the compounds may be administeredin combination with one or more separate pharmaceutical agents, e.g., achemotherapeutic agent, an immunotherapeutic agent, or an adjunctivetherapeutic agent.

Methods of Treatment

The compounds according to the invention as described supra havepreventive and therapeutic utility in human and veterinary diseases.

Thus, in a further aspect the present invention provides the use of thecompounds as described herein and the use of the pharmaceuticalcomposition described herein for preventive and/or therapeutic purposes.

In one embodiment of the present invention, the compounds according tothe invention as described herein or the pharmaceutical composition asdescribed herein may be used as a medicament, preferably for use inhuman medicine and/or veterinarian medicine. Accordingly the presentinvention provides the compounds according to the invention as describedherein or a pharmaceutical composition as described herein, for use as amedicament.

In another embodiment, the compounds according to the invention asdescribed herein or the pharmaceutical composition as described hereinmay be used in a method for preventing or treating cancer in a subject.

Also provided is the use of the compounds according to the invention asdescribed herein or the pharmaceutical composition as described hereinfor the manufacture of a medicament for the prevention or treatment ofcancer in a subject.

Also provided is the use of the compounds according to the invention asdescribed herein or the pharmaceutical composition as described hereinfor the prevention or treatment of cancer in a subject.

Also provided is a method for the prevention or treatment of cancer in asubject, comprising administering to said subject a therapeuticallyeffective amount of the compounds according to the invention asdescribed herein or the pharmaceutical composition as described herein.

The terms “treatment”/“treating” as used herein includes: (1) delayingthe appearance of clinical symptoms of the state, disorder or conditiondeveloping in an animal, particularly a mammal and especially a human,that may be afflicted with or predisposed to the state, disorder orcondition but does not yet experience or display clinical or subclinicalsymptoms of the state, disorder or condition; (2) inhibiting the state,disorder or condition (e.g. arresting, reducing or delaying thedevelopment of the disease, or a relapse thereof in case of maintenancetreatment, of at least one clinical or subclinical symptom thereof);and/or (3) relieving the condition (i.e. causing regression of thestate, disorder or condition or at least one of its clinical orsubclinical symptoms). The benefit to a patient to be treated is eitherstatistically significant or at least perceptible to the patient or tothe physician. However, it will be appreciated that when a medicament isadministered to a patient to treat a disease, the outcome may not alwaysbe effective treatment.

Preventive treatments comprise prophylactic treatments. In preventiveapplications, the pharmaceutical combination of the invention isadministered to a subject suspected of having, or at risk for developingcancer. In therapeutic applications, the pharmaceutical combination isadministered to a subject such as a patient already suffering fromcancer, in an amount sufficient to cure or at least partially arrest thesymptoms of the disease. Amounts effective for this use will depend onthe severity and course of the disease, previous therapy, the subject'shealth status and response to the drugs, and the judgment of thetreating physician.

In the case wherein the subject's condition does not improve, thepharmaceutical combination of the invention may be administeredchronically, which is, for an extended period of time, includingthroughout the duration of the subject's life in order to ameliorate orotherwise control or limit the symptoms of the subject's disease orcondition.

In the case wherein the subject's status does improve, thepharmaceutical combination may be administered continuously;alternatively, the dose of drugs being administered may be temporarilyreduced or temporarily suspended for a certain length of time (i.e., a“drug holiday”). Once improvement of the patient's condition hasoccurred, a maintenance dose of the pharmaceutical combination of theinvention is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, is optionally reduced, as afunction of the symptoms, to a level at which the improved disease isretained.

When provided preventively, the compound(s) are provided in advance ofestablished disease. The preventive administration of a compound of thepresent invention serves to prevent or attenuate the evolution ofdisease. The therapeutic administration of a compound of the presentinvention serves to attenuate established disease. Thus, in accordancewith the invention, a compound of the present invention can beadministered either prior to the onset of disease or during the courseof disease.

In one embodiment of the invention, there is provided the compoundsaccording to the invention as described supra or the pharmaceuticalcomposition as described supra, for use in a method for the preventionor treatment of cancer in a subject. Preferably the cancer is selectedfrom the group consisting of head cancer and neck cancer.

P300

Dysregulation of the cellular transcription machinery is a fundamentalfeature of cancer. E1A binding protein (p300) and CREB binding protein(CBP) are two closely related paralog transcriptional co-activatorsinvolved in the expression of oncogenic drivers in cancer cells (Attarand Kurdistani in Cold Spring Harbor Perspectives in Medicine 7:a026534(2017)).

P300/CBP interact through their conserved domains with hundreds ofproteins; can act synergistically or antagonistically; and modulatedownstream biological processes in a highly context-dependent manner topromote either apoptosis or cell proliferation (Bedford and co-workersin Epigenetics 5(1): 9 (2010); Goodman and Smolik in Genes & Development14(13):1553 (2000); Dancy and Cole in Chemical Reviews 115(6):2419(2015)). These domains include the nuclear receptor interaction domain(RID), the cysteine/histidine regions CH1 (TAZ1) and CH3 (TAZ2), theCREB and MYB interaction domain (KIX), Bromodomain, the planthomeodomain (PHD), the histone acetyltransferase and/or lysineacetyltransferase domain (KAT/HAT), the ZZ type zinc finger domain (ZZ),and the interferon response binding domain (IBiD (NCBD)).

The following examples (from Dancy and Cole in Chemical Reviews115(6):2419 (2015)) demonstrate the context-dependency of geneexpression regulation by p300/CBP. For instance, Hottiger and co-workers(in EMBO Journal 17, 3124 (1998)) showed that HIV gene expression couldbe upregulated by tumor-necrosis factor alpha through binding of theRelA subunit of NFκB to p300/CBP-CH1 but was repressed throughinterferon-alpha-mediated binding of STAT2 to the same motif. In otherstudies, p300/CBP mediated both induction and repression of antioxidantresponse genes, via AP-1 binding to the C-terminal region, respectivelyby p53-binding to CH1/CH3 and glucocorticoid receptor-binding to theNRID domain (Avantaggiati and co-workers in Cell 89:1175 (1997); Kameiand co-workers in Cell 85:403 (1996)). P53 binding to p300/CBP/CH3 andconsequent induction of p53-dependent genes results in cell cycle arrest(e.g., as a consequence of genotoxic insults), but apoptosis is inducedwhen overexpressed E2F-1 (a central protein in cell cycle regulationthat can act through p53 as well) is bound to p300/CBP/CH3 (Goodman andSmolik in Genes & Development 14:1553 (2000); Lee and co-workers inOncogene 16:2695 (1998)). Cyclic-AMP response is both induced andrepressed by p300/CBP via CREB binding to the KIX domain, respectivelyS6 kinase pp90RSK binding to the CH3 domain (Nakajima and co-workers inCell 86:465 (1996)).

Modulation of cancer-relevant pathways by p300/CBP includehormone-dependent androgen receptor signaling in prostate cancer (Culigin Journal of Cell Physiology 231(2):270 (2016)); the HIF-1 alpha/VEGFpathway in hypoxia-dependent tumor growth (Masoud and Li in ActaPharmacologica Sinica B 5(5):378 (2015)); and the interaction with tumorsuppressor p53 and HPV-E6 oncoprotein in HPV-positive carcinomas(Tornesello and co-workers in Cancers (Basel) 10(7)pii:E213 (2018)).

P300 and CBP also play an important role in hematopoiesis and controlprocesses whose disruption can lead to the development of leukemias andlymphomas (Blobel in Blood 95(3):745 (2000); Dutta and co-workers inMolecular Genetics and Metabolism 119(1-2):37 (2016)).

Taken together, these studies highlight how indispensable p300/CBP is tomany cellular signaling pathways and how p300 and CBP utilize theirprotein-protein interactions to determine how the cell responds toenvironmental stimuli. This makes CBP/p300 an ideal target for thedevelopment of novel cancer therapies (Di Martile and co-workers inOncotarget 7(34):55789 (2016); Ali and co-workers in Chemical Reviews118(3):1216 (2018)).

Exploitation of CBP/p300 protein-protein interactions for drug discoveryhas nonetheless proven difficult because of the inherent highlydisordered nature of the protein structure (Wright and Dyson in NatureReviews in Molecular and Cell Biology 16(1): 18-29 (2015)). Yet specificinhibitors have been developed against highly conserved, more ordereddomains such as the HAT/KAT catalytic site, KIX and bromodomain (Breenand Mapp in Current Opinion in Chemical Biology 45:195-203 (2018); Dancyand Cole in Chemical Reviews 115(6):2419-2452 (2015)).

Without being bound by any particular theory, an extremelywell-conserved p300/CBP domain that can be a suitable drug target is thetranscriptional adaptor and zinc finger 1 CH1/TAZ1 domain, ashighlighted by several publications showing e.g. that the interactionbetween p300/CBP-CH1/TAZ1 and HIF 1-alpha as well as the interactionbetween HPV-E6/E7 and p300/CBP-CH1/TAZ1 in HPV-positive Cervical andHead-and-Neck cancer can potentially be exploited for the development ofanticancer therapies (Wuchano Yuan and Giordano in Oncogene21:2253-2260(2002); Breen and Mapp in Current Opinion in ChemicalBiology 45:195-203 (2018); Lao and co-workers in PNAS 111(21):7531(2014); Kushal and co-workers in PNAS 110(39):15602 (2013); Masoud andLi in Acta Pharmacologica Sinica B 5(5):378 (2015); Burslem andco-workers in Chemical Science 8(6):4188 (2017); Fera and co-workers inBiochemistry 51 (47):9524 (2012); Xie and co-workers in Oncogene33(8):1037 (2014); Patel and co-workers in The EMBO Journal 18(18):5061(1999); Bernat and co-workers in Oncogene 22(39):7871 (2003)).

In summary, reprogramming the transcriptional profile of cancer cells bymodulation of p300/CBP activity—for example by targeting the CH1/TAZ1domain—represents a novel and broadly applicable approach for thetreatment of cancer.

Without being bound by any particular theory, compounds of thedisclosure can inhibit or modify the activity of p300 by inhibiting ormodifying the activity of any p300 domain. For example, compounds of thedisclosure can inhibit or modify the activity of the CH1/TAZ1, CH2/TAZ2,RID, KIX, KAT/HAT, PHD, Bromodomain, ZZ or IBiD domains. Compounds ofthe disclosure can inhibit or modify the interaction of p300 with anyone of its protein interaction partners, or combination of proteininteraction partners, through the CH1/TAZ1, CH2/TAZ2, RID, KIX, IBiD orany other p300 protein-protein interaction domain. A non-limiting listof p300 interaction partners whose interaction with p300 can be affectedby compounds of the disclosure includes transcription coactivator BCL3(BCL3), beta-catenin, breast cancer 1, early onset (BRCA1), caudal typehomeobox 2 (CDX2), CCAAT enhancer binding protein beta (CEBPB) and CCAATenhancer binding protein epsilon (CEBPE), Cbp/p300 interactingtransactivator with Glu/Asp rich carboxy-terminal domain 1 (CITED 1),Cbp/p300 interacting transactivator with Glu/Asp rich carboxy-terminaldomain 2 (CITED2), DEAD-box helicase 5 (DDX5), deltex E3 ubiquitinligase 1 (DTX1), EP300 interacting inhibitor of differentiation 1(EID1), ELK1, ETS transcription factor (ELK1), estrogen receptor 1(ESR1), flap structure-specific endonuclease 1 (FEN1), G protein pathwaysuppressor 2 (GPS2), hypoxia inducible factor 1 subunit alpha (HIF1A),HNF1 homeobox A (HNF1A), heterogeneous nuclear ribonucleoprotein U(HNRPU), inhibitor of growth family member 4 (ING4), inhibitor of growthfamily member 5 (ING5), interferon regulatory factor 2 (IRF2), lymphoidenhancer binding factor 1 (LEF 1), MAF bZIP transcription factor (MAF),mastermind like transcriptional coactivator 1 (MAML1), myocyte enhancerfactor 2C (MEF2C), myocyte enhancer factor 2D (MEF2D), MYBproto-oncogene like 2 (MYBL2), MDM2 proto-oncogene (Mdm2), myogenicdifferentiation 1 (MyoD), myocyte enhancer factor 2A (MEF2A), nuclearreceptor coactivator 6 (NCOA6), nuclear factor of activated T cells 2(NFATC2), neuronal PAS domain protein 2 (NPAS2), tumor protein p53(P53), paired box 6 (PAX6), proliferating cell nuclear antigen (PCNA),prospero homeobox 1 (PROX1), prothymosin alpha (PTMA), peroxisomeproliferator activated receptor alpha (PPARA), peroxisome proliferatoractivated receptor gamma (PPARG), RAR related orphan receptor A (RORA),RELA proto-oncogene, NF-kB subunit (RELA), SMAD family member 1 (SMAD1),SMAD family member 2 (SMAD2), MAD family member 7 (SMAD7), Smad nuclearinteracting protein 1 (SNIP1), SS18, nBAF chromatin remodeling complexsubunit (SS18), signal transducer and activator of transcription 3(STAT3), signal transducer and activator of transcription 6 (STAT6), TALbHLH transcription factor 1, erythroid differentiation factor (TAL1),transcription factor 3 (TCF3), transcription factor AP-2 alpha (TFAP2A),trimethylguanosine synthase 1 (TGS1), transcriptional regulating factor1 (TRERF1), tumor susceptibility 101 (TSG101), twist family bHLHtranscription factor 1 (TWIST1), YY1 transcription factor (YY1) andearly growth response 1 (Zif-268).

Without wishing to be bound by any particular theory, inhibiting ormodifying the ability of p300 to interact with protein-proteininteraction partners can inhibit or modify the ability of p300 orprotein complexes comprising p300 to bind to DNA. For example, acompound of the disclosure can prevent p300 or a protein complexcomprising p300 from binding to a target promoter, thereby preventingtranscription of a target gene. A compound of the disclosure can preventp300 or protein complexes comprising p300 from binding to a subset ofall p300 target promoters, thereby altering the transcriptional profileof a cell, for example a cancer cell. Alternatively, or in addition, acompound of the disclosure can inhibit or modify the ability of p300 ora p300 protein complex to recruit one or more additional transcriptionfactors, for example, transcription co-activators, to a promoter.Without limiting the possible pathways affected, a compound of thedisclosure can alter the expression of genes involved in cell cycleprogression, Wnt, Notch and Hedgehog signaling, DNA damage response,apoptosis, antioxidant response, Cyclic-AMP response, hormone-dependentandrogen receptor signaling, hypoxia-dependent tumor growth,hematopoiesis or a combination thereof, thereby reducing theproliferation of or otherwise reducing the viability of cancer cells.For example, compounds of the disclosure can inhibit p300 interactionwith CBP-HPVE6-p53, thereby rescuing p53 protein expression andacetylation and restoring the DNA damage response pathway in cervicalcancer cells. Alternatively, or in addition, compounds of the disclosurecan inhibit the formation of the p300/CBP-HIF1alpha protein complex, andreducing the transcription of growth factors and pro-proliferation genessuch as vascular endothelial growth factor A (VEGF) in cancer cells.Alternatively, or in addition, compounds of the disclosure can disruptp300-CH1/TAZ1 androgen receptor (AR) in castration resistant prostatecancers inhibiting the expression of AR target genes.

Without wishing to be bound by any particular theory, compounds of thedisclosure can inhibit the activity of p300 in its regulation ofoncogenic transcription factors that contribute to cancer progression.

Without wishing to be bound by any particular theory, compounds of thedisclosure can act by inhibiting or modifying the acetyltransferaseactivity of the KAT/HAT domain.

An exemplary human p300 protein sequence can be found in NCBINP_001420.2, the contents of which are hereby incorporated by referencein their entirety. An exemplary human p300 protein comprises a sequenceof:

(SEQ ID NO: 1)    1maenvvepgp psakrpklss palsasasdg tdfgslfdle hdlpdelins telgltnggd   61inqlqtslgm vqdaaskhkq lsellrsgss pnlnmgvggp gqvmasqaqq sspglglins  121mvkspmtqag ltspnmgmgt sgpnqgptqs tgmmnspvnq pamgmntgmn agmnpgmlaa  181gngqgimpnq vmngsigagr grqnmqypnp gmgsagnllt eplqqgspqm ggqtglrgpq  241plkmgmmnnp npygspytqn pgqqigasgl glqiqtktvl snnlspfamd kkavpgggmp  301nmgqqpapqv qqpglvtpva qgmgsgahta dpekrkliqq qlvlllhahk cqrreqange  361vrqcnlphcr tmknvlnhmt hcqsgkscqv ahcassrqii shwknctrhd cpvclplkna  421gdkrnqqpil tgapvglgnp sslgvgqqsa pnlstvsqid pssierayaa lglpyqvnqm  481ptqpqvqakn qqnqqpgqsp qgmrpmsnms aspmgvnggv gvqtpsllsd smlhsainsq  541npmmsenasv pslgpmptaa qpsttgirkq wheditqdlr nhlvhklvqa ifptpdpaal  601kdrrmenlva yarkvegdmy esannraeyy hllaekiyki qkeleekrrt rlqkqnmlpn  661aagmvpvsmn pgpnmgqpqp gmtsngplpd psmirgsvpn qmmpritpqs glnqfgqmsm  721aqppivprqt pplqhhgqla qpgalnppmg ygprmqqpsn qgqflpqtqf psqgmnvtni  781plapssgqap vsqaqmssss cpvnspimpp gsqgshihcp qlpgpalhqn spspvpsrtp  841tphhtppsig aqqppattip apvptppamp pgpqsqalhp pprqtptppt tqlpqqvqps  901lpaapsadqp qqqprsqqst aasvptptap llppqpatpl sqpavsiegq vsnppstsst  961evnsqaiaek qpsqevkmea kmevdqpepa dtqpedises kvedckmest eteerstelk 1021teikeeedqp stsatqsspa pgqskkkifk peelrqalmp tlealyrqdp eslpfrqpvd 1081pqllgipdyf divkspmdls tikrkldtgq yqepwqyvdd iwlmfnnawl ynrktsrvyk 1141ycsklsevfe qeidpvmqsl gyccgrklef spqtlccygk qlctiprdat yysyqnryhf 1201cekcfneiqg esyslgddps qpqttinkeq fskrkndtld pelfvectec grkmhqicvl 1261hheiiwpagf vcdgclkksa rtrkenkfsa krlpstrlgt flenrvndfl rrqnhpesge 1321vtvrvvhasd ktvevkpgmk arfvdsgema esfpyrtkal fafeeidgvd loffgmhvqe 1381ygsdcpppnq rrvyisylds vhffrpkclr tavyheilig yleyvkklgy ttghiwacpp 1441segddyifhc hppdqkipkp krlqewykkm ldkavseriv hdykdifkqa tedrltsake 1501lpyfegdfwp nvleesikel eqeeeerkre entsnestdv tkgdsknakk knnkktsknk 1561sslsrgnkkk pgmpnvsndl sqklyatmek hkevffvirl iagpaanslp pivdpdplip 1621cdlmdgrdaf ltlardkhle fsslrraqws tmcmlvelht qsqdrfvytc neckhhvetr 1681whctvcedyd lcitcyntkn hdhkmeklgl glddesnnqq aaatqspgds rrlsiqrciq 1741slvhacqcrn ancslpscqk mkrvvqhtkg ckrktnggcp ickqlialcc yhakhcqenk 1801cpvpfclnik qklrqqqlqh rlqqaqmlrr rmasmqrtgv vgqqqglpsp tpatpttptg 1861qqpttpqtpq ptsqpqptpp nsmppylprt qaagpvsqgk aagqvtpptp pqtaqpplpg 1921pppaavemam qiqraaetqr qmahvqifqr piqhqmppmt pmapmgmnpp pmtrgpsghl 1981epgmgptgmq qqppwsqggl pqpqqlqsgm prpammsvaq hgqplnmapq pglgqvgisp 2041lkpgtvsqqa lqnllrtlrs pssplqqqqv lsilhanpql laafikqraa kyansnpqpi 2101pgqpgmpqgq pglqpptmpg qqgvhsnpam gnmnpmqagv qraglpqqqp qqqlqppmgg 2161mspqaqqmnm nhntmpsqfr dilrrqqmmq qqqqqgagpg igpgmanhnq fqqpqgvgyp 2221pqqqqrmqhh mqqmqqgnmg qigqlpqalg aeagaslqay qqrllqqqmg spvqpnpmsp 2281qqhmlpnqaq sphlqgqqip nslsnqvrsp qpvpsprpqs qpphsspspr mqpqpsphhv 2341spqtssphpg lvaaqanpme qghfaspdqn smlsqlasnp gmanlhgasa tdlglstdns 2401dlnsnlsqst ldih.

In some embodiments, a p300 protein comprises a protein having at least85% identity to SEQ ID NO: 1, at least 90% identity to SEQ ID NO: 1, atleast 95% identity to SEQ ID NO: 1, 50 at least 96% identity to SEQ IDNO: 1, at least 97% identity to SEQ ID NO: 1, at least 98% identity toSEQ ID NO: 1, at least 99% identity to SEQ ID NO: 1 or at least 99.8%identity to SEQ ID NO: 1. In some embodiments, a p300 protein isidentical to a protein of SEQ ID NO: 1.

The CH1/TAZ domain corresponds approximately to amino acids 347-414 ofSEQ ID NO: 1. The KIX domain corresponds approximately to amino acids566-646 of SEQ ID NO: 1. The bromodomain corresponds approximately toamino acids 1051-1158 of SEQ ID NO: 1. The PHD domain correspondsapproximately to amino acids 1243-1277 of SEQ ID NO: 1. The HAT/KATdomain corresponds approximately to amino acids 1306-1612 of SEQ IDNO: 1. The ZZ domain corresponds approximately to amino acids 1668-1708of SEQ ID NO: 1. The TAZ2 domain corresponds approximately to aminoacids 1729-1807 of SEQ ID NO: 1.

As used herein in the context of polypeptides, nucleic acids, andchemical compounds, the term “corresponding to”, designates theposition/identity of a structural element, e.g., of an amino acidresidue, a nucleotide residue, or a chemical moiety, in a compound orcomposition through comparison with an appropriate reference compound orcomposition. For example, in some embodiments, a monomeric residue in apolymer (e.g., an amino acid residue in a polypeptide or a nucleic acidresidue in a polynucleotide) may be identified as “corresponding to” aresidue in an appropriate reference polymer. For example, those ofordinary skill will appreciate that, for purposes of simplicity,residues in a polypeptide are often designated using a canonicalnumbering system based on a reference related polypeptide, so that anamino acid “corresponding to” a residue at position 190, for example,need not actually be the 190th amino acid in a particular amino acidchain but rather corresponds to the residue found at position 190 in thereference polypeptide; those of ordinary skill in the art readilyappreciate how to identify “corresponding” amino acids (see. e.g.,Benson et al. Nucl. Acids Res. (1 Jan. 2013) 41 (Dl): D36-D42; Pearsonet al. PNAS Vol. 85, pp. 2444-2448, April 1988). Those skilled in theart will be aware of various sequence alignment strategies, includingsoftware programs such as, for example, BLAST, CS-BLAST, CUSASW++,DIAMOND, FASTA, GGSEARCH/GLSEARCH, Genoogle, HMMER, HHpred/HHsearch,IDF, Infernal, KLAST, USEARCH, parasail, PSI-BLAST, PSI-Search,ScalaBLAST, Sequilab, SAM, SSEARCH, SWAPHI, SWAPHI-LS, SWIMM, or SWIPEthat can be utilized, for example, to identify “corresponding” residuesin polypeptides and/or nucleic acids in accordance with the presentdisclosure.

As used herein the term “domain” refers to a section or portion of apolypeptide. In some embodiments, a “domain” is associated with aparticular structural and/or functional feature of the polypeptide sothat, when the domain is physically separated from the rest of itsparent polypeptide, it substantially or entirely retains the particularstructural and/or functional feature. In some embodiments, a domain mayinclude a portion of a polypeptide that, when separated from that(parent) polypeptide and linked with a different (recipient)polypeptide, substantially retains and/or imparts on the recipientpolypeptide one or more structural and/or functional features thatcharacterized it in the parent polypeptide. In some embodiments, adomain is a section of a polypeptide. In some such embodiments, a domainis characterized by a particular structural element (e.g., a particularamino acid sequence or sequence motif, oc-helix character, b-sheetcharacter, coiled-coil character, random coil character), and/or by aparticular functional feature (e.g., binding activity, enzymaticactivity, folding activity, signaling activity). One of ordinary skillwill appreciate that domain boundaries are typically determinedexperimentally or via sequence alignment, and may be approximate. Insome embodiments, domain boundaries may vary by at least 1, at least 2,at least 3, at least 4, at least 5, at least 6, at least 10, at least 15or at least 20 amino acids without affecting the in vivo function of thedomain.

An exemplary nucleic acid sequence encoding a p300 protein comprises asequence of:

(SEQ ID NO: 2)    1gagaaggagg aggacagcgc cgaggaggaa gaggttgatg gcggcggcgg agctccgaga   61gacctcggct gggcaggggc cggccgtggc gggccgggga ctgcgcctct agagccgcga  121gttctcggga attcgccgca gcggacgcgc tcggcgaatt tgtgctcttg tgccctcctc  181cgggcttggg cccaggcccg gcccctcgca cttgccctta ccttttctat cgagtccgca  241tccctctcca gccactgcga cccggcgaag agaaaaagga acttccccca ccccctcggg  301tgccgtcgga gccccccagc ccacccctgg gtgcggcgcg gggaccccgg gccgaagaag  361agatttcctg aggattctgg ttttcctcgc ttgtatctcc gaaagaatta aaaatggccg  421agaatgtggt ggaaccgggg ccgccttcag ccaagcggcc taaactctca tctccggccc  481tctcggcgtc cgccagcgat ggcacagatt ttggctctct atttgacttg gagcacgact  541taccagatga attaatcaac tctacagaat tgggactaac caatggtggt gatattaatc  601agcttcagac aagtcttggc atggtacaag atgcagcttc taaacataaa cagctgtcag  661aattgctgcg atctggtagt tcccctaacc tcaatatggg agttggtggc ccaggtcaag  721tcatggccag ccaggcccaa cagagcagtc ctggattagg tttgataaat agcatggtca  781aaagcccaat gacacaggca ggcttgactt ctcccaacat ggggatgggc actagtggac  841caaatcaggg tcctacgcag tcaacaggta tgatgaacag tccagtaaat cagcctgcca  901tgggaatgaa cacagggatg aatgcgggca tgaatcctgg aatgttggct gcaggcaatg  961gacaagggat aatgcctaat caagtcatga acggttcaat tggagcaggc cgagggcgac 1021agaatatgca gtacccaaac ccaggcatgg gaagtgctgg caacttactg actgagcctc 1081ttcagcaggg ctctccccag atgggaggac aaacaggatt gagaggcccc cagcctctta 1141agatgggaat gatgaacaac cccaatcctt atggttcacc atatactcag aatcctggac 1201agcagattgg agccagtggc cttggtctcc agattcagac aaaaactgta ctatcaaata 1261acttatctcc atttgctatg gacaaaaagg cagttcctgg tggaggaatg cccaacatgg 1321gtcaacagcc agccccgcag gtccagcagc caggcctggt gactccagtt gcccaaggga 1381tgggttctgg agcacataca gctgatccag agaagcgcaa gctcatccag cagcagcttg 1441ttctcctttt gcatgctcac aagtgccagc gccgggaaca ggccaatggg gaagtgaggc 1501agtgcaacct tccccactgt cgcacaatga agaatgtcct aaaccacatg acacactgcc 1561agtcaggcaa gtcttgccaa gtggcacact gtgcatcttc tcgacaaatc atttcacact 1621ggaagaattg tacaagacat gattgtcctg tgtgtctccc cctcaaaaat gctggtgata 1681agagaaatca acagccaatt ttgactggag cacccgttgg acttggaaat cctagctctc 1741taggggtggg tcaacagtct gcccccaacc taagcactgt tagtcagatt gatcccagct 1801ccatagaaag agcctatgca gctcttggac taccctatca agtaaatcag atgccgacac 1861aaccccaggt gcaagcaaag aaccagcaga atcagcagcc tgggcagtct ccccaaggca 1921tgcggcccat gagcaacatg agtgctagtc ctatgggagt aaatggaggt gtaggagttc 1981aaacgccgag tcttctttct gactcaatgt tgcattcagc cataaattct caaaacccaa 2041tgatgagtga aaatgccagt gtgccctccc tgggtcctat gccaacagca gctcaaccat 2101ccactactgg aattcggaaa cagtggcacg aagatattac tcaggatctt cgaaatcatc 2161ttgttcacaa actcgtccaa gccatatttc ctacgccgga tcctgctgct ttaaaagaca 2221gacggatgga aaacctagtt gcatatgctc ggaaagttga aggggacatg tatgaatctg 2281caaacaatcg agcggaatac taccaccttc tagctgagaa aatctataag atccagaaag 2341aactagaaga aaaacgaagg accagactac agaagcagaa catgctacca aatgctgcag 2401gcatggttcc agtttccatg aatccagggc ctaacatggg acagccgcaa ccaggaatga 2461cttctaatgg ccctctacct gacccaagta tgatccgtgg cagtgtgcca aaccagatga 2521tgcctcgaat aactccacaa tctggtttga atcaatttgg ccagatgagc atggcccagc 2581cccctattgt accccggcaa acccctcctc ttcagcacca tggacagttg gctcaacctg 2641gagctctcaa cccgcctatg ggctatgggc ctcgtatgca acagccttcc aaccagggcc 2701agttccttcc tcagactcag ttcccatcac agggaatgaa tgtaacaaat atccctttgg 2761ctccgtccag cggtcaagct ccagtgtctc aagcacaaat gtctagttct tcctgcccgg 2821tgaactctcc tataatgcct ccagggtctc aggggagcca cattcactgt ccccagcttc 2881ctcaaccagc tcttcatcag aattcaccct cgcctgtacc tagtcgtacc cccacccctc 2941accatactcc cccaagcata ggggctcagc agccaccagc aacaacaatt ccagcccctg 3001ttcctacacc tcctgccatg ccacctgggc cacagtccca ggctctacat ccccctccaa 3061ggcagacacc tacaccacca acaacacaac ttccccaaca agtgcagcct tcacttcctg 3121ctgcaccttc tgctgaccag ccccagcagc agcctcgctc acagcagagc acagcagcgt 3181ctgttcctac cccaacagca ccgctgcttc ctccgcagcc tgcaactcca ctttcccagc 3241cagctgtaag cattgaagga caggtatcaa atcctccatc tactagtagc acagaagtga 3301attctcaggc cattgctgag aagcagcctt cccaggaagt gaagatggag gccaaaatgg 3361aagtggatca accagaacca gcagatactc agccggagga tatttcagag tctaaagtgg 3421aagactgtaa aatggaatct accgaaacag aagagagaag cactgagtta aaaactgaaa 3481taaaagagga ggaagaccag ccaagtactt cagctaccca gtcatctccg gctccaggac 3541agtcaaagaa aaagattttc aaaccagaag aactacgaca ggcactgatg ccaactttgg 3601aggcacttta ccgtcaggat ccagaatccc ttccctttcg tcaacctgtg gaccctcagc 3661ttttaggaat ccctgattac tttgatattg tgaagagccc catggatctt tctaccatta 3721agaggaagtt agacactgga cagtatcagg agccctggca gtatgtcgat gatatttggc 3781ttatgttcaa taatgcctgg ttatataacc ggaaaacatc acgggtatac aaatactgct 3841ccaagctctc tgaggtcttt gaacaagaaa ttgacccagt gatgcaaagc cttggatact 3901gttgtggcag aaagttggag ttctctccac agacactgtg ttgctacggc aaacagttgt 3961gcacaatacc tcgtgatgcc acttattaca gttaccagaa caggtatcat ttctgtgaga 4021agtgtttcaa tgagatccaa ggggagagcg tttctttggg ggatgaccct tcccagcctc 4081aaactacaat aaataaagaa caattttcca agagaaaaaa tgacacactg gatcctgaac 4141tgtttgttga atgtacagag tgcggaagaa agatgcatca gatctgtgtc cttcaccatg 4201agatcatctg gcctgctgga ttcgtctgtg atggctgttt aaagaaaagt gcacgaacta 4261ggaaagaaaa taagttttct gctaaaaggt tgccatctac cagacttggc acctttctag 4321agaatcgtgt gaatgacttt ctgaggcgac agaatcaccc tgagtcagga gaggtcactg 4381ttagagtagt tcatgcttct gacaaaaccg tggaagtaaa accaggcatg aaagcaaggt 4441ttgtggacag tggagagatg gcagaatcct ttccataccg aaccaaagcc ctctttgcct 4501ttgaagaaat tgatggtgtt gacctgtgct tctttggcat gcatgttcaa gagtatggct 4561ctgactgccc tccacccaac cagaggagag tatacatatc ttacctcgat agtgttcatt 4621tcttccgtcc taaatgcttg aggactgcag tctatcatga aatcctaatt ggatatttag 4681aatatgtcaa gaaattaggt tacacaacag ggcatatttg ggcatgtcca ccaagtgagg 4741gagatgatta tatcttccat tgccatcctc ctgaccagaa gatacccaag cccaagcgac 4801tgcaggaatg gtacaaaaaa atgcttgaca aggctgtatc agagcgtatt gtccatgact 4861acaaggatat ttttaaacaa gctactgaag atagattaac aagtgcaaag gaattgcctt 4921atttcgaggg tgatttctgg cccaatgttc tggaagaaag cattaaggaa ctggaacagg 4981aggaagaaga gagaaaacga gaggaaaaca ccagcaatga aagcacagat gtgaccaagg 5041gagacagcaa aaatgctaaa aagaagaata ataagaaaac cagcaaaaat aagagcagcc 5101tgagtagggg caacaagaag aaacccggga tgcccaatgt atctaacgac ctctcacaga 5161aactatatgc caccatggag aagcataaag aggtcttctt tgtgatccgc ctcattgctg 5221gccctgctgc caactccctg cctcccattg ttgatcctga tcctctcatc ccctgcgatc 5281tgatggatgg tcgggatgcg tttctcacgc tggcaaggga caagcacctg gagttctctt 5341cactccgaag agcccagtgg tccaccatgt gcatgctggt ggagctgcac acgcagagcc 5401aggaccgctt tgtctacacc tgcaatgaat gcaagcacca tgtggagaca cgctggcact 5461gtactgtctg tgaggattat gacttgtgta tcacctgcta taacactaaa aaccatgacc 5521acaaaatgga gaaactaggc cttggcttag atgatgagag caacaaccag caggctgcag 5581ccacccagag cccaggcgat tctcgccgcc tgagtatcca gcgctgcatc cagtctctgg 5641tccatgcttg ccagtgtcgg aatgccaatt gctcactgcc atcctgccag aagatgaagc 5701gggttgtgca gcataccaag ggttgcaaac ggaaaaccaa tggcgggtgc cccatctgca 5761agcagctcat tgccctctgc tgctaccatg ccaagcactg ccaggagaac aaatgcccgg 5821tgccgttctg cctaaacatc aagcagaagc tccggcagca acagctgcag caccgactac 5881agcaggccca aatgcttcgc aggaggatgg ccagcatgca gcggactggt gtggttgggc 5941agcaacaggg cctcccttcc cccactcctg ccactccaac gacaccaact ggccaacagc 6001caaccacccc gcagacgccc cagcccactt ctcagcctca gcctacccct cccaatagca 6061tgccacccta cttgcccagg actcaagctg ctggccctgt gtcccagggt aaggcagcag 6121gccaggtgac ccctccaacc cctcctcaga ctgctcagcc accccttcca gggcccccac 6181ctgcagcagt ggaaatggca atgcagattc agagagcagc ggagacgcag cgccagatgg 6241cccacgtgca aatttttcaa aggccaatcc aacaccagat gcccccgatg actcccatgg 6301cccccatggg tatgaaccca cctcccatga ccagaggtcc cagtgggcat ttggagccag 6361ggatgggacc gacagggatg cagcaacagc caccctggag ccaaggagga ttgcctcagc 6421cccagcaact acagtctggg atgccaaggc cagccatgat gtcagtggcc cagcatggtc 6481aacctttgaa catggctcca caaccaggat tgggccaggt aggtatcagc ccactcaaac 6541caggcactgt gtctcaacaa gccttacaaa accttttgcg gactctcagg tctcccagct 6601ctcccctgca gcagcaacag gtgcttagta tccttcacgc caacccccag ctgttggctg 6661cattcatcaa gcagcgggct gccaagtatg ccaactctaa tccacaaccc atccctgggc 6721agcctggcat gccccagggg cagccagggc tacagccacc taccatgcca ggtcagcagg 6781gggtccactc caatccagcc atgcagaaca tgaatccaat gcaggcgggc gttcagaggg 6841ctggcctgcc ccagcagcaa ccacagcagc aactccagcc acccatggga gggatgagcc 6901cccaggctca gcagatgaac atgaaccaca acaccatgcc ttcacaattc cgagacatct 6961tgagacgaca gcaaatgatg caacagcagc agcaacaggg agcagggcca ggaataggcc 7021ctggaatggc caaccataac cagttccagc aaccccaagg agttggctac ccaccacagc 7081agcagcagcg gatgcagcat cacatgcaac agatgcaaca aggaaatatg ggacagatag 7141gccagcttcc ccaggccttg ggagcagagg caggtgccag tctacaggcc tatcagcagc 7201gactccttca gcaacagatg gggtcccctg ttcagcccaa ccccatgagc ccccagcagc 7261atatgctccc aaatcaggcc cagtccccac acctacaagg ccagcagatc cctaattctc 7321tctccaatca agtgcgctct ccccagcctg tcccttctcc acggccacag tcccagcccc 7381cccactccag tccttcccca aggatgcagc ctcagccttc tccacaccac gtttccccac 7441agacaagttc cccacatcct ggactggtag ctgcccaggc caaccccatg gaacaagggc 7501attttgccag cccggaccag aattcaatgc tttctcagct tgctagcaat ccaggcatgg 7561caaacctcca tggtgcaagc gccacggacc tgggactcag caccgataac tcagacttga 7621attcaaacct ctcacagagt acactagaca tacactagag acaccttgta gtattttggg 7681agcaaaaaaa ttattttctc ttaacaagac tttttgtact gaaaacaatt tttttgaatc 7741tttcgtagcc taaaagacaa ttttccttgg aacacataag aactgtgcag tagccgtttg 7801tggtttaaag caaacatgca agatgaacct gagggatgat agaatacaaa gaatatattt 7861ttgttatggc tggttaccac cagcctttct tcccctttgt gtgtgtggtt caagtgtgca 7921ctgggaggag gctgaggcct gtgaagccaa acaatatgct cctgccttgc acctccaata 7981ggttttatta ttttttttaa attaatgaac atatgtaata ttaatagtta ttatttactg 8041gtgcagatgg ttgacatttt tccctatttt cctcacttta tggaagagtt aaaacatttc 8101taaaccagag gacaaaaggg gttaatgtta ctttaaaatt acattctata tatatataaa 8161tatatataaa tatatattaa aataccagtt ttttttctct gggtgcaaag atgttcattc 8221ttttaaaaaa tgtttaaaaa aaaaaaaaaa ctgcctttct tcccctcaag tcaacttttg 8281tgctccagaa aattttctat tctgtaagtc tgagcgtaaa acttcaagta ttaaaataat 8341ttgtacatgt agagagaaaa atgacttttt caaaaatata caggggcagc tgccaaattg 8401atgtattata tattgtggtt tctgtttctt gaaagaattt ttttcgttat ttttacatct 8461aacaaagtaa aaaaattaaa aagagggtaa gaaacgattc cggtgggatg attttaacat 8521gcaaaatgtc cctgggggtt tcttctttgc ttgctttctt cctccttacc ctacccccca 8581ctcacacaca cacacacaca cacacacaca cacacacaca cacactttct ataaaacttg 8641aaaatagcaa aaaccctcaa ctgttgtaaa tcatgcaatt aaagttgatt acttataaat 8701atgaactttg gatcactgta tagactgtta aatttgattt cttattacct attgttaaat 8761aaactgtgtg agacagaca.

In some embodiments, a nucleic acid sequence encoding a p300 proteincomprises a nucleic acid sequence encoding a protein having at least 85%identity to SEQ ID NO:1, at least 90% identity to SEQ ID NO: 1, at least95% identity to SEQ ID NO: 1, at least 96% identity to SEQ ID NO: 1, atleast 97% identity to SEQ ID NO: 1, at least 98% identity to SEQ ID NO:1, at least 99% identity to SEQ ID NO: 1 or at least 99.8% identity toSEQ ID NO: 1. In some embodiments, nucleic acid sequence encoding a p300protein comprises a nucleic acid sequence encoding a protein identicalto SEQ ID NO: 1. In some embodiments, a nucleic acid sequence encoding ap300 protein comprises a nucleic acid sequence e having at least 85%identity to SEQ ID NO: 2, at least 90% identity to SEQ ID NO: 2, atleast 95% identity to SEQ ID NO: 2, at least 96% identity to SEQ ID NO:2, at least 97% identity to SEQ ID NO: 2, at least 98% identity to SEQID NO: 2, at least 99% identity to SEQ ID NO: 2 or at least 99.8%identity to SEQ ID NO: 2. In some embodiments, a nucleic acid sequenceencoding a p300 protein comprises a nucleic acid sequence identical toSEQ ID NO: 2 or a portion or subsequence thereof.

As used herein, the term “expression” of a nucleic acid sequence refersto the generation of any gene product from the nucleic acid sequence. Insome embodiments, a gene product can be a transcript. In someembodiments, a gene product can be a polypeptide. In some embodiments,expression of a nucleic acid sequence involves one or more of thefollowing: (1) production of an RNA template from a DNA sequence (e.g.,by transcription); (2) processing of an RNA transcript (e.g., bysplicing, editing, 5′ cap formation, and/or 3′ end formation); (3)translation of an RNA into a polypeptide or protein; and/or (4)post-translational modification of a polypeptide or protein.

As used herein, the term “nucleic acid” refers to a polymer of at leastthree nucleotides. In some embodiments, a nucleic acid comprises DNA. Insome embodiments comprises RNA. In some embodiments, a nucleic acid issingle stranded. In some embodiments, a nucleic acid is double stranded.In some embodiments, a nucleic acid comprises both single and doublestranded portions. In some embodiments, a nucleic acid comprises abackbone that comprises one or more phosphodiester linkages. In someembodiments, a nucleic acid comprises a backbone that comprises bothphosphodiester and non-phosphodiester linkages. In some embodiments, anucleic acid comprises one or more, or all, natural residues (e.g.,adenine, cytosine, deoxyadenosine, deoxycytidine, deoxyguanosine,deoxythymidine, guanine, thymine, uracil). In some embodiments, anucleic acid comprises on or more, or all, non-natural residues. In someembodiments, a non-natural residue comprises a nucleoside analog. Insome embodiments, a nucleic acid has a nucleotide sequence that encodesa functional gene product such as an RNA or polypeptide. In someembodiments, a nucleic acid has a nucleotide sequence that comprises oneor more introns. In some embodiments, a nucleic acid may be prepared byisolation from a natural source, enzymatic synthesis (e.g., bypolymerization based on a complementary template, e.g., in vivo or invitro, reproduction in a recombinant cell or system, or chemicalsynthesis).

Methods of Treating Cancer

Cancer is a disease caused by the uncontrolled division of cells in thebody. Abnormally dividing cancer cells can form a primary tumor, whichcan then invade nearby tissues, and spread throughout the body throughthe blood and lymphatic systems (metastatic cancers). Cancer can arisefrom many organs and cell types in the body, including but not limitedto, cells of the lymphatic system, bone marrow, blood, brain and nervoussystem tissue, breast, cervix, ovary, colorectal cells, stomach andgastric cells, head and neck, kidney, liver, lung, oesophagus, pancreas,prostate and skin.

As used herein, the term “tumor” refers to an abnormal growth of cellsor tissue. In some embodiments, a tumor may comprise cells that areprecancerous (e.g., benign), malignant, pre-metastatic, metastatic,and/or non-metastatic. In some embodiments, a tumor is associated with,or is a manifestation of, a cancer.

In some embodiments, a tumor may be a disperse tumor or a liquid tumor.Liquid tumors can affect bone marrow, blood cells and the lymphaticsystem. Exemplary liquid tumors include leukemias and lymphomas. Typesof lymphomas include, but are not limited to, Hodgkin lymphomas,non-Hodgkin lymphomas, B cell lymphomas, T-cell lymphomas, Burkitt'slymphomas, mantle cell lymphomas, small lymphocytic lymphomas,histiocytic lymphomas and primary mediastinal B cell lymphomas. Types ofleukemias include, but are not limited to, acute myeloid leukemia, Tcell leukemias, acute lymphoblastic leukemias and chronic myelogenousleukemias.

In some embodiments, a tumor may be a solid tumor. Exemplary solidtumors include, but are not limited to Carcinomas, Sarcomas, Myelomas,germ cell tumors, carcinoid tumors, neuroendocrine tumors and tumors ofmixed type (a tumor which comprises multiple types of cancer cells).Carcinomas arise from epithelial tissues, either internal or external,such as cells of the gastrointestinal tract. Exemplary carcinomasinclude adenocarcinoma, which develops in an organ or gland, andsquamous cell carcinoma, which originates in the squamous epithelium.Sarcomas are cancers that originate in supportive or connective tissuessuch as bones, tendons, cartilage, muscle and fat. Exemplary sarcomasinclude osteosarcoma, chondrosarcoma, leiomyosarcoma, rhabdomyosarcoma,mesothelial sarcoma, fibrosarcoma, angiosarcoma, liposarcoma, glioma orastrocytoma, myxosarcoma and mesenchymous or mixed mesodermal tumors.

Tumors can arise from most organs and tissue in the body, including, butnot limited to, brain and nervous tissue, breast, cervix, ovary, uterus,colorectal, stomach and gastric tissue, kidney, liver, lung oesophagus,pancreas, prostate, skin, bone, head and neck, and lung. Exemplary brainand nervous system cancers include neurogliomas and glioblastomas.Exemplary breast cancers include human breast carcinomas, breastadenocarcinomas and invasive ductal carcinomas. Exemplary cervicalcancers include epidermoid carcinomas, cervical carcinomas and HPVpositive cervical cancers. Exemplary ovarian cancers include ovariancarcinomas. Exemplary colorectal cancers include colorectal carcinomasand colon colorectal adenocarcinomas. Exemplary stomach and gastriccancers include gastric adenocarcinomas, stomach adenocarcinomas andgastric carcinomas. Exemplary kidney cancers include renal celladenocarcinomas and kidney clear cell carcinomas. Exemplary livercancers include hepatocellular carcinomas and hepatomas. Exemplary lungcancers include small cell lung cancers, non-small cell lung cancers,lung carcinomas, lung adenocarcinomas, squamous cell carcinomas andlarge cell carcinomas. Exemplary esophageal cancers include esophagealsquamous cell carcinoma. Exemplary pancreatic cancers include pancreaticcarcinoma and pancreatic ductal adenocarcinoma. Exemplary prostatecancers include prostate carcinomas, prostate adenocarcinomas andcastrate resistant prostate cancers. Exemplary skin cancers includemelanomas, squamous cell carcinomas and basal cell carcinomas. Exemplaryhead and neck cancers include squamous cell carcinomas.

As used herein, the term “subject” refers to an organism, for example, amammal (e.g., a human, a non-human mammal, a non-human primate, aprimate, a laboratory animal, a mouse, a rat, a hamster, a gerbil, acat, a dog). In some embodiments a human subject is an adult,adolescent, or pediatric subject (a child). In some embodiments, asubject is suffering from a disease, disorder or condition, e.g., adisease, disorder or condition that can be treated as provided herein,e.g., a cancer or a tumor listed herein. In some embodiments, a subjectdisplays one or more symptoms of a disease, disorder or condition. Insome embodiments, a subject does not display a particular symptom (e.g.,clinical manifestation of disease) or characteristic of a disease,disorder, or condition. In some embodiments, a subject does not displayany symptom or characteristic of a disease, disorder, or condition. Insome embodiments, a subject is a patient. In some embodiments, a subjectis an individual to whom diagnosis and/or therapy is and/or has beenadministered.

A cancer that is to be treated can be staged according to the AmericanJoint Committee on Cancer (AJCC) TNM classification system, where thetumor (T) has been assigned a stage of TX, T1, T1mic, T1a, Tib, Tic, T2,T3, T4, T4a, T4b, T4c, or T4d; and where the regional lymph nodes (N)have been assigned a stage of NX, NO, Ni, N2, N2a, N2b, N3, N3a, N3b, orN3c; and where distant metastasis (M) can be assigned a stage of MX, MO,or Ml. A cancer that is to be treated can be staged according to anAmerican Joint Committee on Cancer (AJCC) classification as Stage I,Stage IIA, Stage IIB, Stage IIIA, Stage IIIB, Stage IIIC, or Stage IV. Acancer that is to be treated can be assigned a grade according to anAJCC classification as Grade GX (e.g., grade cannot be assessed), Grade1, Grade 2, Grade 3 or Grade 4. A cancer that is to be treated can bestaged according to an AJCC pathologic classification (pN) of pNX, pNO,PNO (I−), PNO (I+), PNO (mol−), PNO (mol+), PN1, PN1(mi), PN1a, PN1b,PN1c, pN2, pN2a, pN2b, pN3, pN3a, pN3b, or pN3c.

A cancer that is to be treated can be evaluated by DNA cytometry, flowcytometry, or image cytometry. A cancer that is to be treated can betyped as having 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cellsin the synthesis stage of cell division (e.g., in S phase of celldivision). A cancer that is to be treated can be typed as having a lowS-phase fraction or a high S-phase fraction.

As used herein, a “normal cell” is a cell that cannot be classified aspart of a “cell proliferative disorder”. A normal cell lacks unregulatedor abnormal growth, or both, that can lead to the development of anunwanted condition or disease. Preferably, a normal cell possessesnormally functioning cell cycle checkpoint control mechanisms.

As used herein, “contacting a cell” refers to a condition in which acompound or other composition of matter is in direct contact with acell, or is close enough to induce a desired biological effect in acell.

As used herein, “monotherapy” refers to the administration of a singleactive or therapeutic compound to a subject in need thereof. Preferably,monotherapy will involve administration of a therapeutically effectiveamount of an active compound. For example, cancer monotherapy with oneof the compound of the present invention, or a pharmaceuticallyacceptable salt, polymorph, solvate, analog or derivative thereof, to asubject in need of treatment of cancer. Monotherapy may be contrastedwith combination therapy, in which a combination of multiple activecompounds is administered, preferably with each component of thecombination present in a therapeutically effective amount. In oneaspect, monotherapy with a compound of the present invention, or apharmaceutically acceptable salt, polymorph or solvate thereof, is moreeffective than combination therapy in inducing a desired biologicaleffect.

As used herein, “treating” or “treat” describes the management and careof a patient for the purpose of combating a disease, condition, ordisorder and includes the administration of a compound of the presentinvention, or a pharmaceutically acceptable salt, polymorph or solvatethereof, to alleviate one or more symptoms or complications of adisease, condition or disorder, or to eliminate the disease, conditionor disorder. The term “treat” can also include treatment of a cell invitro or an animal model.

A compound of the present invention, or a pharmaceutically acceptablesalt, polymorph or solvate thereof, can also be used to prevent adisease, condition or disorder, or used to identify suitable candidatesfor such purposes. As used herein, “preventing” or “prevent” describesreducing or eliminating the onset of the symptoms or complications ofthe disease, condition or disorder.

As used herein, the term “alleviate” is meant to describe a process bywhich the severity of a sign or symptom of a disorder is decreased.Importantly, a sign or symptom can be alleviated without beingeliminated. In a preferred embodiment, the administration ofpharmaceutical compositions of the invention leads to the elimination ofa sign or symptom, however, elimination is not required. Effectivedosages are expected to decrease the severity of a sign or symptom. Forinstance, a sign or symptom of a disorder such as cancer, which canoccur in multiple locations, is alleviated if the severity of the canceris decreased within at least one of multiple locations.

As used herein, the term “severity” is meant to describe the potentialof cancer to transform from a precancerous, or benign, state into amalignant state. Alternatively, or in addition, severity is meant todescribe a cancer stage, for example, according to the TNM system(accepted by the International Union Against Cancer (UICC) and theAmerican Joint Committee on Cancer (AJCC)) or by other art-recognizedmethods. Cancer stage refers to the extent or severity of the cancer,based on factors such as the location of the primary tumor, tumor size,number of tumors, and lymph node involvement (spread of cancer intolymph nodes). Alternatively, or in addition, severity is meant todescribe the tumor grade by art-recognized methods (see, National CancerInstitute, www.cancer.gov). Tumor grade is a system used to classifycancer cells in terms of how abnormal they look under a microscope andhow quickly the tumor is likely to grow and spread. Many factors areconsidered when determining tumor grade, including the structure andgrowth pattern of the cells. The specific factors used to determinetumor grade vary with each type of cancer. Severity also describes ahistologic grade, also called differentiation, which refers to how muchthe tumor cells resemble normal cells of the same tissue type (see,National Cancer Institute, www.cancer.gov). Furthermore, severitydescribes a nuclear grade, which refers to the size and shape of thenucleus in tumor cells and the percentage of tumor cells that aredividing (see, National Cancer Institute, www.cancer.gov).

In another aspect of the invention, severity describes the degree towhich a tumor has secreted growth factors, degraded the extracellularmatrix, become vascularized, lost adhesion to juxtaposed tissues, ormetastasized. Moreover, severity describes the number of locations towhich a primary tumor has metastasized. Finally, severity includes thedifficulty of treating tumors of varying types and locations. Forexample, inoperable tumors, those cancers which have greater access tomultiple body systems (hematological and immunological tumors), andthose which are the most resistant to traditional treatments areconsidered most severe. In these situations, prolonging the lifeexpectancy of the subject and/or reducing pain, decreasing theproportion of cancerous cells or restricting cells to one system, andimproving cancer stage/tumor grade/histological grade/nuclear grade areconsidered alleviating a sign or symptom of the cancer.

As used herein the term “symptom” is defined as an indication ofdisease, illness, injury, or that something is not right in the body.Symptoms are felt or noticed by the individual experiencing the symptom,but may not easily be noticed by others. Others are defined asnon-health-care professionals.

As used herein the term “sign” is also defined as an indication thatsomething is not right in the body. But signs are defined as things thatcan be seen by a doctor, nurse, or other health care professional.

Cancer is a group of diseases that may cause almost any sign or symptom.The signs and symptoms will depend on where the cancer is, the size ofthe cancer, and how much it affects the nearby organs or structures. Ifa cancer spreads (metastasizes), then symptoms may appear in differentparts of the body.

Treating cancer can result in a reduction in size of a tumor. Areduction in size of a tumor may also be referred to as “tumorregression”. Preferably, after treatment, tumor size is reduced by 5% orgreater relative to its size prior to treatment; more preferably, tumorsize is reduced by 10% or greater; more preferably, reduced by 20% orgreater; more preferably, reduced by 30% or greater; more preferably,reduced by 40% or greater; even more preferably, reduced by 50% orgreater; and most preferably, reduced by greater than 75% or greater.Size of a tumor may be measured by any reproducible means ofmeasurement. The size of a tumor may be measured as a diameter of thetumor.

Treating cancer can result in a reduction in tumor volume. Preferably,after treatment, tumor volume is reduced by 5% or greater relative toits size prior to treatment; more preferably, tumor volume is reduced by10% or greater; more preferably, reduced by 20% or greater; morepreferably, reduced by 30% or greater; more preferably, reduced by 40%or greater; even more preferably, reduced by 50% or greater; and mostpreferably, reduced by greater than 75% or greater. Tumor volume may bemeasured by any reproducible means of measurement.

Treating cancer results in a decrease in number of tumors. Preferably,after treatment, tumor number is reduced by 5% or greater relative tonumber prior to treatment; more preferably, tumor number is reduced by10% or greater; more preferably, reduced by 20% or greater; morepreferably, reduced by 30% or greater; more preferably, reduced by 40%or greater; even more preferably, reduced by 50% or greater; and mostpreferably, reduced by greater than 75%. Number of tumors may bemeasured by any reproducible means of measurement. The number of tumorsmay be measured by counting tumors visible to the naked eye or at aspecified magnification. Preferably, the specified magnification is 2×,3×, 4×, 5×, 10×, or 50×.

Treating cancer can result in a decrease in number of metastatic lesionsin other tissues or organs distant from the primary tumor site.Preferably, after treatment, the number of metastatic lesions is reducedby 5% or greater relative to number prior to treatment; more preferably,the number of metastatic lesions is reduced by 10% or greater; morepreferably, reduced by 20% or greater; more preferably, reduced by 30%or greater; more preferably, reduced by 40% or greater; even morepreferably, reduced by 50% or greater; and most preferably, reduced bygreater than 75%. The number of metastatic lesions may be measured byany reproducible means of measurement. The number of metastatic lesionsmay be measured by counting metastatic lesions visible to the naked eyeor at a specified magnification. Preferably, the specified magnificationis 2×, 3×, 4×, 5×, 10×, or 50×.

Treating cancer can result in an increase in average survival time of apopulation of treated subjects in comparison to a population receivingcarrier alone. Preferably, the average survival time is increased bymore than 30 days; more preferably, by more than 60 days; morepreferably, by more than 90 days; and most preferably, by more than 120days. An increase in average survival time of a population may bemeasured by any reproducible means. An increase in average survival timeof a population may be measured, for example, by calculating for apopulation the average length of survival following initiation oftreatment with an active compound. An increase in average survival timeof a population may also be measured, for example, by calculating for apopulation the average length of survival following completion of afirst round of treatment with an active compound.

Treating cancer can result in an increase in average survival time of apopulation of treated subjects in comparison to a population ofuntreated subjects. Preferably, the average survival time is increasedby more than 30 days; more preferably, by more than 60 days; morepreferably, by more than 90 days; and most preferably, by more than 120days. An increase in average survival time of a population may bemeasured by any reproducible means. An increase in average survival timeof a population may be measured, for example, by calculating for apopulation the average length of survival following initiation oftreatment with an active compound. An increase in average survival timeof a population may also be measured, for example, by calculating for apopulation the average length of survival following completion of afirst round of treatment with an active compound.

Treating cancer can result in increase in average survival time of apopulation of treated subjects in comparison to a population receivingmonotherapy with a drug that is not a compound of the present invention,or a pharmaceutically acceptable salt, polymorph, solvate, analog orderivative thereof. Preferably, the average survival time is increasedby more than 30 days; more preferably, by more than 60 days; morepreferably, by more than 90 days; and most preferably, by more than 120days. An increase in average survival time of a population may bemeasured by any reproducible means. An increase in average survival timeof a population may be measured, for example, by calculating for apopulation the average length of survival following initiation oftreatment with an active compound. An increase in average survival timeof a population may also be measured, for example, by calculating for apopulation the average length of survival following completion of afirst round of treatment with an active compound.

Treating cancer can result in a decrease in the mortality rate of apopulation of treated subjects in comparison to a population receivingcarrier alone. Treating cancer can result in a decrease in the mortalityrate of a population of treated subjects in comparison to an untreatedpopulation. Treating cancer can result in a decrease in the mortalityrate of a population of treated subjects in comparison to a populationreceiving monotherapy with a drug that is not a compound of the presentinvention, or a pharmaceutically acceptable salt, polymorph, solvate,analog or derivative thereof. Preferably, the mortality rate isdecreased by more than 2%; more preferably, by more than 5%; morepreferably, by more than 10%; and most preferably, by more than 25%. Adecrease in the mortality rate of a population of treated subjects maybe measured by any reproducible means. A decrease in the mortality rateof a population may be measured, for example, by calculating for apopulation the average number of disease-related deaths per unit timefollowing initiation of treatment with an active compound. A decrease inthe mortality rate of a population may also be measured, for example, bycalculating for a population the average number of disease-relateddeaths per unit time following completion of a first round of treatmentwith an active compound.

Treating cancer can result in a decrease in tumor growth rate.Preferably, after treatment, tumor growth rate is reduced by at least 5%relative to number prior to treatment; more preferably, tumor growthrate is reduced by at least 10%; more preferably, reduced by at least20%; more preferably, reduced by at least 30%; more preferably, reducedby at least 40%; more preferably, reduced by at least 50%; even morepreferably, reduced by at least 50%; and most preferably, reduced by atleast 75%. Tumor growth rate may be measured by any reproducible meansof measurement. Tumor growth rate can be measured according to a changein tumor diameter per unit time.

Treating cancer can result in a decrease in tumor regrowth. Preferably,after treatment, tumor regrowth is less than 5%; more preferably, tumorregrowth is less than 10%; more preferably, less than 20%; morepreferably, less than 30%; more preferably, less than 40%; morepreferably, less than 50%; even more preferably, less than 50%; and mostpreferably, less than 75%. Tumor regrowth may be measured by anyreproducible means of measurement. Tumor regrowth is measured, forexample, by measuring an increase in the diameter of a tumor after aprior tumor shrinkage that followed treatment. A decrease in tumorregrowth is indicated by failure of tumors to reoccur after treatmenthas stopped.

Treating cancer can result in a reduction in the rate of cellularproliferation.

Preferably, after treatment, the rate of cellular proliferation isreduced by at least 5%; more preferably, by at least 10%; morepreferably, by at least 20%; more preferably, by at least 30%; morepreferably, by at least 40%; more preferably, by at least 50%; even morepreferably, by at least 50%; and most preferably, by at least 75%. Therate of cellular proliferation may be measured by any reproducible meansof measurement. The rate of cellular proliferation is measured, forexample, by measuring the number of dividing cells in a tissue sampleper unit time.

Treating cancer can result in a reduction in the proportion ofproliferating cells. Preferably, after treatment, the proportion ofproliferating cells is reduced by at least 5%; more preferably, by atleast 10%; more preferably, by at least 20%; more preferably, by atleast 30%; more preferably, by at least 40%; more preferably, by atleast 50%; even more preferably, by at least 50%; and most preferably,by at least 75%. The proportion of proliferating cells may be measuredby any reproducible means of measurement. Preferably, the proportion ofproliferating cells is measured, for example, by quantifying the numberof dividing cells relative to the number of non dividing cells in atissue sample. The proportion of proliferating cells can be equivalentto the mitotic index.

Treating cancer can result in a decrease in size of an area or zone ofcellular proliferation. Preferably, after treatment, size of an area orzone of cellular proliferation is reduced by at least 5% relative to itssize prior to treatment; more preferably, reduced by at least 10%; morepreferably, reduced by at least 20%; more preferably, reduced by atleast 30%; more preferably, reduced by at least 40%; more preferably,reduced by at least 50%; even more preferably, reduced by at least 50%;and most preferably, reduced by at least 75%. Size of an area or zone ofcellular proliferation may be measured by any reproducible means ofmeasurement. The size of an area or zone of cellular proliferation maybe measured as a diameter or width of an area or zone of cellularproliferation.

Treating cancer can result in a decrease in the number or proportion ofcells having an abnormal appearance or morphology. Preferably, aftertreatment, the number of cells having an abnormal morphology is reducedby at least 5% relative to its size prior to treatment; more preferably,reduced by at least 10%; more preferably, reduced by at least 20%; morepreferably, reduced by at least 30%; more preferably, reduced by atleast 40%; more preferably, reduced by at least 50%; even morepreferably, reduced by at least 50%; and most preferably, reduced by atleast 75%. An abnormal cellular appearance or morphology may be measuredby any reproducible means of measurement. An abnormal cellularmorphology can be measured by microscopy, e.g., using an inverted tissueculture microscope. An abnormal cellular morphology can take the form ofnuclear pleiomorphism.

Treating cancer can result in cell death, and preferably, cell deathresults in a decrease of at least 10% in number of cells in apopulation. More preferably, cell death means a decrease of at least20%; more preferably, a decrease of at least 30%; more preferably, adecrease of at least 40%; more preferably, a decrease of at least 50%;most preferably, a decrease of at least 75%. Number of cells in apopulation may be measured by any reproducible means. A number of cellsin a population can be measured by fluorescence activated cell sorting(FACS), immunofluorescence microscopy and light microscopy. Methods ofmeasuring cell death are as shown in Li et al., Proc Natl Acad Sci USA.100(5): 2674-8, 2003. In an aspect, cell death occurs by apoptosis.

As used herein, the term “selectively” means tending to occur at ahigher frequency in one population than in another population. Thecompared populations can be cell populations. Preferably, a compound ofthe present invention, or a pharmaceutically acceptable salt, polymorphor solvate thereof, acts selectively on a cancer or precancerous cellbut not on a normal cell. Preferably, a compound of the presentinvention, or a pharmaceutically acceptable salt, polymorph or solvatethereof, acts selectively to modulate one molecular target (e.g., p300)but does not significantly modulate another molecular target (e.g., anon-target protein). The invention also provides a method forselectively inhibiting the activity of a protein such as p300.Preferably, an event occurs selectively in population A relative topopulation B if it occurs greater than two times more frequently inpopulation A as compared to population B. An event occurs selectively ifit occurs greater than five times more frequently in population A. Anevent occurs selectively if it occurs greater than ten times morefrequently in population A; more preferably, greater than fifty times;even more preferably, greater than 100 times; and most preferably,greater than 1000 times more frequently in population A as compared topopulation B. For example, cell death would be said to occur selectivelyin cancer cells if it occurred greater than twice as frequently incancer cells as compared to normal cells.

A compound of the present invention, or a pharmaceutically acceptablesalt, polymorph or solvate thereof, can modulate the activity of amolecular target (e.g., p300). Modulating refers to stimulating orinhibiting an activity of a molecular target. Preferably, a compound ofthe present invention, or a pharmaceutically acceptable salt, polymorphor solvate thereof, modulates the activity of a molecular target if itstimulates or inhibits the activity of the molecular target by at least2-fold relative to the activity of the molecular target under the sameconditions but lacking only the presence of said compound. Morepreferably, a compound of the present invention, or a pharmaceuticallyacceptable salt, polymorph or solvate thereof, modulates the activity ofa molecular target if it stimulates or inhibits the activity of themolecular target by at least 5-fold, at least 10-fold, at least 20-fold,at least 50-fold, at least 100-fold relative to the activity of themolecular target under the same conditions but lacking only the presenceof said compound. The activity of a molecular target may be measured byany reproducible means. The activity of a molecular target may bemeasured in vitro or in vivo. For example, the activity of a moleculartarget may be measured in vitro by an enzymatic activity assay or a DNAbinding assay, or the activity of a molecular target may be measured invivo by assaying for expression of a reporter gene.

A compound of the present invention, or a pharmaceutically acceptablesalt, polymorph or solvate thereof, does not significantly modulate theactivity of a molecular target if the addition of the compound does notstimulate or inhibit the activity of the molecular target by greaterthan 10% relative to the activity of the molecular target under the sameconditions but lacking only the presence of said compound.

Preferably, a compound of the present invention, or a pharmaceuticallyacceptable salt, polymorph or solvate thereof, demonstrates thisdifferential across the range of inhibition, and the differential isexemplified at the IC₅₀, i.e., a 50% inhibition, for a molecular targetof interest.

Administering a compound of the present invention, or a pharmaceuticallyacceptable salt, polymorph or solvate thereof, to a cell or a subject inneed thereof can result in modulation (i.e., stimulation or inhibition)of an activity of a protein of interest.

Administering a compound of the present invention, or a pharmaceuticallyacceptable salt, polymorph or solvate thereof, to a cell or a subject inneed thereof results in modulation (i.e., stimulation or inhibition) ofan activity of an intracellular target (e.g., substrate).

Preferably, an effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, polymorph or solvate thereof, isnot significantly cytotoxic to normal cells. A therapeutically effectiveamount of a compound is not significantly cytotoxic to normal cells ifadministration of the compound in a therapeutically effective amountdoes not induce cell death in greater than 10% of normal cells. Atherapeutically effective amount of a compound does not significantlyaffect the viability of normal cells if administration of the compoundin a therapeutically effective amount does not induce cell death ingreater than 10% of normal cells. In an aspect, cell death occurs byapoptosis.

Contacting a cell with a compound of the present invention, or apharmaceutically acceptable salt, polymorph or solvate thereof, caninduce or activate cell death selectively in cancer cells. Administeringto a subject in need thereof a compound of the present invention, or apharmaceutically acceptable salt, polymorph or solvate thereof, caninduce or activate cell death selectively in cancer cells. Contacting acell with a compound of the present invention, or a pharmaceuticallyacceptable salt, polymorph or solvate thereof, can induce cell deathselectively in one or more cells affected by a cell proliferativedisorder. Preferably, administering to a subject in need thereof acompound of the present invention, or a pharmaceutically acceptablesalt, polymorph or solvate thereof, induces cell death selectively inone or more cells affected by a cell proliferative disorder.

One skilled in the art may refer to general reference texts for detaileddescriptions of known techniques discussed herein or equivalenttechniques. These texts include Ausubel et al, Current Protocols inMolecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al,Molecular Cloning, A Laboratory Manual (3rd edition), Cold Spring HarborPress, Cold Spring Harbor, N.Y. (2000); Coligan et al, Current Protocolsin Immunology, John Wiley & Sons, N.Y.; Enna et al, Current Protocols inPharmacology, John Wiley & Sons, N.Y.; Fingl et al, The PharmacologicalBasis of Therapeutics (1975), Remington's Pharmaceutical Sciences, MackPublishing Co., Easton, Pa., 18^(th) edition (1990). These texts can, ofcourse, also be referred to in making or using an aspect of theinvention.

Dosing Regimen

An exemplary treatment regime entails administration once daily, twicedaily, three times daily, every second day, twice per week, once perweek. The composition of the invention is usually administered onmultiple occasions. Intervals between single dosages can be, forexample, less than a day, daily, every second day, twice per week, orweekly. The composition of the invention may be given as a continuousuninterrupted treatment. In an exemplary treatment regimen the compoundof formula (I) or formula (Ia) according to the invention can beadministered from 0.1-1500 mg per day.

As used herein, the term “therapeutically effective amount” refers to anamount that produces a desired effect (e.g., a desired biological,clinical, or pharmacological effect) in a subject or population to whichit is administered. In some embodiments, the term refers to an amountstatistically likely to achieve the desired effect when administered toa subject in accordance with a particular dosing regimen (e.g., atherapeutic dosing regimen). In some embodiments, the term refers to anamount sufficient to produce the effect in at least a significantpercentage (e.g., at least about 25%, about 30%, about 40%, about 50%,about 60%, about 70%, about 80%, about 90%, about 95%, or more) of apopulation that is suffering from and/or susceptible to a disease,disorder, and/or condition. In some embodiments, a therapeuticallyeffective amount is one that reduces the incidence and/or severity of,and/or delays onset of, one or more symptoms of the disease, disorder,and/or condition. Those of ordinary skill in the art will appreciatethat the term “therapeutically effective amount” does not in factrequire successful treatment be achieved in a particular individual.Rather, a therapeutically effective amount may be an amount thatprovides a particular desired response in a significant number ofsubjects when administered to patients in need of such treatment, e.g.,in at least about 25%, about 30%, about 40%, about 50%, about 60%, about70%, about 80%, about 90%, about 95%, or more patients within a treatedpatient population. In some embodiments, reference to a therapeuticallyeffective amount may be a reference to an amount sufficient to induce adesired effect as measured in one or more specific tissues (e.g., atissue affected by the disease, disorder or condition) or fluids (e.g.,blood, saliva, serum, sweat, tears, urine). Those of ordinary skill inthe art will appreciate that, in some embodiments, a therapeuticallyeffective amount of a particular agent or therapy may be formulatedand/or administered in a single dose. In some embodiments, atherapeutically effective agent may be formulated and/or administered ina plurality of doses, for example, as part of a dosing regimen.

In some embodiments, a compound or pharmaceutical composition for use inaccordance with the present disclosure is formulated, dosed, and/oradministered in a therapeutically effective amount using pharmaceuticalcompositions and dosing regimens that are consistent with good medicalpractice and appropriate for the relevant agent(s) and subject(s). Inprinciple, compounds and pharmaceutical compositions can be administeredby any appropriate method known in the art, including, withoutlimitation, oral, mucosal, by-inhalation, topical, buccal, nasal,rectal, or parenteral (e.g. intravenous, infusion, intratumoral,intranodal, subcutaneous, intraperitoneal, intramuscular, intradermal,transdermal, or other kinds of administration involving physicalbreaching of a tissue of a subject and administration of the therapeuticcomposition through the breach in the tissue). In some embodiments, thecompound or pharmaceutical composition is administered directly to thetumor (e.g., by intratumoral injection).

In some embodiments, a dosing regimen for a particular active agent mayinvolve intermittent or continuous (e.g., by perfusion or other slowrelease system) administration, for example to achieve a particulardesired pharmacokinetic profile or other pattern of exposure in one ormore tissues or fluids of interest in the subject receiving therapy.

In some embodiments, different agents administered in combination may beadministered via different routes of delivery and/or according todifferent schedules. Alternatively or additionally, in some embodiments,one or more doses of a first active agent is administered substantiallysimultaneously with, and in some embodiments via a common route and/oras part of a single composition with, one or more other active agents.

Factors to be considered when optimizing routes and/or dosing schedulefor a given therapeutic regimen may include, for example, the particularindication being treated, the clinical condition of a subject (e.g.,age, overall health, prior therapy received and/or response thereto) thesite of delivery of the agent, the nature of the agent (e.g. an antibodyor other polypeptide-based compound), the mode and/or route ofadministration of the agent, the presence or absence of combinationtherapy, and other factors known to medical practitioners. For example,in the treatment of cancer, relevant features of the indication beingtreated may include, for example, one or more of cancer type, stage,location.

In some embodiments, one or more features of a particular pharmaceuticalcomposition and/or of a utilized dosing regimen may be modified overtime (e.g., increasing or decreasing the amount of active agent in anyindividual dose, increasing or decreasing time intervals between doses),for example in order to optimize a desired therapeutic effect orresponse (e.g., inhibition or modulation of a p300 gene or geneproduct).

In general, type, amount, and frequency of dosing of compounds orpharmaceutical compositions in accordance with the present invention aregoverned by safety and efficacy requirements that apply when one or morerelevant agent(s) is/are administered to a mammal, preferably a human.In general, such features of dosing are selected to provide aparticular, and typically detectable, therapeutic response as comparedto what is observed absent therapy.

In some embodiments, a “therapeutically effective amount” or“therapeutically effective dose” is an amount of a compound orpharmaceutical composition of the disclosure, or a combination of two ormore compounds or pharmaceutical compositions of the disclosure, or acombination of a compound or pharmaceutical composition of thedisclosure with one or more additional therapeutic agent(s), whichinhibits, totally or partially, the progression of the condition oralleviates, at least partially, one or more symptoms of the condition.In some embodiments, a therapeutically effective amount can be an amountwhich is prophylactically effective. In some embodiments, an amountwhich is therapeutically effective may depend upon a patient's sizeand/or gender, the condition to be treated, severity of the conditionand/or the result sought. In some embodiments, a therapeuticallyeffective amount refers to that amount that results in amelioration ofat least one symptom in a patient. In some embodiments, for a givenpatient, a therapeutically effective amount may be determined by methodsknown to those of skill in the art.

In some embodiments, toxicity and/or therapeutic efficacy of a compoundor pharmaceutical composition of the disclosure can be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., for determining the maximum tolerated dose (MTD) and theED₅₀ (effective dose for 50% maximal response). Typically, the doseratio between toxic and therapeutic effects is the therapeutic index; insome embodiments, this ratio can be expressed as the ratio between MTDand ED₅₀. Data obtained from such cell culture assays and animal studiescan be used in formulating a range of dosage for use in humans.

In some embodiments, dosage may be guided by monitoring the effect of acompound or pharmaceutical composition of the disclosure on one or morepharmacodynamic markers of p300 function in diseased or surrogatetissue. For example, cell culture or animal experiments can be used todetermine the relationship between doses required for changes inpharmacodynamic markers such as p300 downstream target genes or p53acetylation and doses required for therapeutic efficacy can bedetermined in cell culture or animal experiments or early stage clinicaltrials. In some embodiments, dosage of a compound or pharmaceuticalcomposition of the disclosure lies preferably within a range ofcirculating concentrations that include the ED₅₀ with little or notoxicity. In some embodiments, dosage may vary within such a range, forexample depending upon the dosage form employed and/or the route ofadministration utilized. The exact formulation, route of administrationand dosage can be chosen by the individual physician in view of thepatient's condition. In the treatment of crises or severe conditions,administration of a dosage approaching the MTD may be required to obtaina rapid response.

In some embodiments, dosage amount and/or interval may be adjustedindividually, for example to provide plasma levels of an active moietywhich are sufficient to maintain, for example a desired effect, or aminimal effective concentration (MEC) for a period of time required toachieve therapeutic efficacy. In some embodiments, MEC for a particularcompound or pharmaceutical composition of the disclosure can beestimated, for example, from in vitro data and/or animal experiments.Dosages necessary to achieve the MEC will depend on individualcharacteristics and route of administration. In some embodiments, highpressure liquid chromatography (HPLC) assays or bioassays can be used todetermine plasma concentrations.

In some embodiments, dosage intervals can be determined using the MECvalue. In certain embodiments, a compound or pharmaceutical compositionof the disclosure should be administered using a regimen which maintainsplasma levels above the MEC for 10-90% of the time, preferably between30-90% and most preferably between 50-90% until the desired ameliorationof a symptom is achieved. In other embodiments, different MEC plasmalevels will be maintained for differing amounts of time. In cases oflocal administration or selective uptake, the effective localconcentration of the drug may not be related to plasma concentration.

One of skill in the art can select from a variety of administrationregimens and will understand that an effective amount of a particular acompound or pharmaceutical composition of the disclosure may bedependent on the subject being treated, on the subject's weight, theseverity of the affliction, the manner of administration and/or thejudgment of the prescribing physician.

Combination Therapy

In some embodiments, compounds or pharmaceutical compositions of thedisclosure can be administered to a subject in need thereof as a cancermonotherapy. Alternatively, or in addition, compounds or pharmaceuticalcompositions of the disclosure can be administered to a subject in needthereof in combination with at least one additional cancer therapy.

In some embodiments, the at least one additional cancer therapycomprises a standard of care for the cancer of the subject. As usedherein, “standard of care” refers to a treatment of a particular cancerthat is accepted by persons of skill in the art as the generallyaccepted treatment for that indication, and whose practice is commonamongst medical professionals. For example, standard of care for primarytumors that can be surgically resected without undue risk to the subjectcomprises surgical removal of the tumor. The person of ordinary skill inthe art will readily understand what is a “standard of care” for aparticular cancer indication.

In some embodiments, the at least one additional cancer therapycomprises surgical resection of the cancer, radiation therapy, or acombination thereof.

In some embodiments, compounds or pharmaceutical compositions of thedisclosure can be used in combination with another therapeutic agent totreat cancer in the subject in a combinational therapy. In someembodiments, the combinational therapy is in addition to a standard ofcare therapies, surgical resection and/or radiation therapy.

In some embodiments, compounds or pharmaceutical compositions of thedisclosure can optionally contain, and/or be administered in combinationwith, one or more additional therapeutic agents, such as a cancertherapeutic agent, e.g., a chemotherapeutic agent or a biological agent.

An additional agent can be, for example, a therapeutic agent that ise.g., an anti-cancer agent, or an agent that ameliorates a symptomassociated with the disease or condition being treated. The additionalagent also can be an agent that imparts a beneficial attribute to thetherapeutic composition (e.g., an agent that affects the viscosity ofthe composition). For example, in some embodiments, compounds orpharmaceutical compositions of the disclosure are administered to asubject who has received, is receiving, and/or will receive therapy withanother therapeutic agent or modality (e.g., with a chemotherapeuticagent, surgery, radiation, or a combination thereof).

Some embodiments of combination therapy modalities provided by thepresent disclosure provide, for example, administration of compounds orpharmaceutical compositions of the disclosure and additional cancertherapeutic agent(s) in a single pharmaceutical formulation.

Some embodiments provide administration of compounds or pharmaceuticalcompositions of the disclosure and administration of additional cancertherapeutic agent(s) in separate pharmaceutical formulations. In someembodiments, the compounds or pharmaceutical compositions of thedisclosure and the additional cancer therapeutic agent are administeredsimultaneously. Simultaneous administration can be by the same modality(e.g., both by oral administration), or by different modalities (e.g.,one oral, one injected). In some embodiments, the compounds orpharmaceutical compositions of the disclosure and the additional cancertherapeutic agent are administered in temporal proximity. For example,the compounds or pharmaceutical compositions of the disclosure and theadditional cancer therapeutic agent are administered within 1 minute, 2minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours,3 hours, 4 hours, 5 hours, 6 hours, 12 hours or 24 hours of each other.In some embodiments, the compounds or pharmaceutical compositions of thedisclosure and the additional cancer therapeutic agent are administeredin sequence. For example, the compounds or pharmaceutical compositionsof the disclosure and the additional cancer therapeutic agent can beadministered in an alternating sequence.

In some embodiments, the at least one additional cancer therapeuticagent comprises a chemotherapeutic agent.

Examples of chemotherapeutic agents that can be used in combination withcompound or pharmaceutical composition described herein include platinumcompounds (e.g., cisplatin, carboplatin, and oxaliplatin), alkylatingagents (e.g., cyclophosphamide, ifosfamide, chlorambucil, nitrogenmustard, thiotepa, melphalan, busulfan, procarbazine, streptozocin,temozolomide, dacarbazine, and bendamustine), antitumor antibiotics(e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, mitoxantrone,bleomycin, mytomycin C, plicamycin, and dactinomycin), taxanes (e.g.,paclitaxel and docetaxel), antimetabolites (e.g., 5-fluorouracil,cytarabine, premetrexed, thioguanine, floxuridine, capecitabine, andmethotrexate), nucleoside analogues (e.g., fludarabine, clofarabine,cladribine, pentostatin, and nelarabine), topoisomerase inhibitors(e.g., topotecan and irinotecan), hypomethylating agents (e.g.,azacitidine and decitabine), proteasome inhibitors (e.g., bortezomib),epipodophyllotoxins (e.g., etoposide and teniposide), DNA synthesisinhibitors (e.g., hydroxyurea), vinca alkaloids (e.g., vincristine,vindesine, vinorelbine, and vinblastine), tyrosine kinase inhibitors(e.g., imatinib, dasatinib, nilotinib, sorafenib, and sunitinib),nitrosoureas (e.g., carmustine, fotemustine, and lomustine),hexamethylmelamine, mitotane, angiogenesis inhibitors (e.g., thalidomideand lenalidomide), steroids (e.g., prednisone, dexamethasone, andprednisolone), hormonal agents (e.g., enzalutamide, tamoxifen,raloxifene, leuprolide, bicalutamide, granisetron, and flutamide),aromatase inhibitors (e.g., letrozole and anastrozole), arsenictrioxide, tretinoin, nonselective cyclooxygenase inhibitors (e.g.,nonsteroidal anti-inflammatory agents, salicylates, aspirin, piroxicam,ibuprofen, indomethacin, naprosyn, diclofenac, tolmetin, ketoprofen,nabumetone, and oxaprozin), selective cyclooxygenase-2 (COX-2)inhibitors, or any combination thereof.

In some embodiments, the additional agent affects (e.g., inhibits)histone modifications, such as histone acetylation or histonemethylation. In certain embodiments, an additional anticancer agent isselected from the group consisting of chemotherapeutics (such as 2CdA,5-FU, 6-Mercaptopurine, 6-TG, Abraxane™, Accutane®, Actinomycin-D,Adriamycin®, Alimta®, all-trans retinoic acid, amethopterin, Ara-C,Azacitadine, BCNU, Blenoxane®, Camptosar®, CeeNU®, Clofarabine, Clolar™,Cytoxan®, daunorubicin hydrochloride, DaunoXome®, Dacogen®, DIC, Doxil®,Ellence®, Eloxatin®, Emcyt®, etoposide phosphate, Fludara®, FUDR®,Gemzar®, Gleevec®, hexamethylmelamine, Hycamtin®, Hydrea®, Idamycin®,Ifex®, ixabepilone, Ixempra®, L-asparaginase, Leukeran®, liposomalAra-C, LPAM, Lysodren, Matulane®, mithracin, Mitomycin-C, Myleran®,Navelbine®, Neutrexin®, nilotinib, Nipent®, Nitrogen Mustard,Novantrone®, Oncaspar®, Panretin®, Paraplatin®, Platinol®,prolifeprospan 20 with carmustine implant, Sandostatin®, Targretin®,Tasigna®, Taxotere®, Temodar®, TESPA, Trisenox®, Valstar®, Velban®,Vidaza™, vincristine sulfate, VM 26, Xeloda® and Zanosar®); biologies(such as Alpha Interferon, Bacillus Calmette-Guerin, Bexxar®, Campath®,Ergamisol®, Erlotinib, Herceptin®, Interleukin-2, Iressa®, lenalidomide,Mylotarg®, Ontak®, Pegasys®, Revlimid®, Rituxan®, Tarceva™, Thalomid®,Velcade® and Zevalin™); small molecules (such as Tykerb®);corticosteroids (such as dexamethasone sodium phosphate, DeltaSone® andDelta-Cortef®); hormonal therapies (such as Arimidex®, Aromasin®,Casodex®, Cytadren®, Eligard®, Eulexin®, Evista®, Faslodex®, Femara®,Halotestin®, Megace®, Nilandron®, Nolvadex®, Plenaxis™ and Zoladex®);and radiopharmaceuticals (such as Iodotope®, Metastron®, Phosphocol® andSamarium SM-153).

Examples of biological agents that can be used in combination with thecompositions and methods described herein include monoclonal antibodies(e.g., rituximab, cetuximab, obinutuzumab, ofatumumab, ibritumomab,brentuximab, bevacizumab, panitumumab, pembrolizumab, tositumomab,trastuzumab, alemtuzumab, gemtuzumab ozogamicin, bevacizumab,catumaxomab, denosumab, obinutuzumab, ofatumumab, ramucirumab,pertuzumab, ipilimumab, nivolumab, nimotuzumab, lambrolizumab,pidilizumab, siltuximab, tremelimumab, or others known in the art),enzymes (e.g., L-asparaginase), cytokines (e.g., interferons andinterleukins), growth factors (e.g., colony stimulating factors anderythropoietin) or inhibitors thereof, cancer vaccines, gene therapyvectors, or any combination thereof. In some embodiments, the growthfactor inhibitor comprises an inhibitor of vascular endothelial growthfactor A (VEGFA). In some embodiments, the inhibitor of VEGFA comprisesAvastin® (bevacizumab).

In some embodiments, biological agents comprise adoptive cell therapies.For example, chimeric antigen receptor T cell (CAR-T) therapies. In someembodiments, the adoptive cell therapy is autologous. In someembodiments, the adoptive cell therapy is allogeneic.

In some embodiments, the at least one additional cancer therapeuticagent comprises an immune checkpoint inhibitor. Immune checkpointinhibitors target immune checkpoints, which regulate the immune system,and under certain circumstances, can prevent the immune system fromtargeting tumors. In some embodiments, the immune checkpoint comprises aPD-1/PD-L1 immune checkpoint. In some embodiments, the immune checkpointcomprises a CLTA-4 immune checkpoint. In some embodiments, the immunecheckpoint inhibitor is an antibody or a small molecule. Exemplary PD-1inhibitors include, but are not limited, nivolumab and pembrolizumab.Exemplary PD-L1 inhibitors include, but are not limited to,atezolizumab, avelumab and durvalumab. Exemplary CLTA-4 inhibitorsinclude, but are not limited to, ipilimumab.

The additional agents that can be used in combination with compositionsand methods of the disclosure as set forth above are for illustrativepurposes and not intended to be limiting. The combinations embraced bythis disclosure, include, without limitation, one or more compounds orpharmaceutical compositions as provided herein and at least oneadditional agent selected from the categories or lists above orotherwise provided herein. The compounds and pharmaceutical compositionsof the disclosure can also be used in combination with one or with morethan one additional agent, e.g., with two, three, four, five, or six, ormore, additional agents.

In some embodiments, treatment methods described herein are performed onsubjects for which other treatments of the medical condition have failedor have had less success in treatment through other means, e.g., insubjects having a cancer refractory to standard-of-care treatment.Additionally, the treatment methods described herein can be performed inconjunction with one or more additional treatments of the medicalcondition, e.g., in addition to or in combination with standard-of-caretreatment. For instance, the method can comprise administering a cancerregimen, e.g., nonmyeloablative chemotherapy, surgery, hormone therapy,and/or radiation, prior to, substantially simultaneously with, intemporal proximity to, in sequence with or after the administration of acompound or pharmaceutical composition described herein.

Additional Methods

The invention encompasses methods comprising providing at least onecompound, measuring the activity of the compound and determining if theactivity of the compound is above or below a predetermined level.

Methods of measuring the activity of a compound will be readily apparentto one of ordinary skill in the art. Exemplary methods include measuringgrowth-inhibitory concentration (GI50) in vitro in a cell proliferationassay or a colony survival assay. Cell proliferation can be measuredusing any technique known in the art. For example, cell proliferationcan be measured by measuring colony formation using stains such asCrystal Violet/DBPS and measuring 600 nm absorbance. Alternatively, orin addition, cells can be treated with a dye that permeabilizes thecells and reacts with certain enzymes to provide a measure of metabolicactivity (for example, MTT or WST-1). Proliferation can be measuredusing fluorescence dyes such as CyQUANT (ThermoFisher Scientific).Alternatively, or in addition, cell proliferation can be measured byexamining one or more proliferation markers, such as BrdU incorporationor proliferating cell nuclear antigen (PCNA) expression.

Alternatively, or in addition, the method of measuring activity of acompound of the disclosure comprises measuring an effect of the compoundon tumor growth in an animal. Exemplary animal cancer models include,but are not limited to, patient derived xenograft (PDX) cancer models,transgenic models and gene knock out or gene knock in models that modifyone or more tumor suppressor or oncogenes and syngeneic models. In a PDXmodel, cancer cells derived from a patient or cell line isolated orderived from a cancer of interest are transplanted into an immunedeficient animal. In some embodiments, the immune deficient animal is aseverely compromised immune deficient (SCID) mouse, a NOD-SCID mouse, ora recombination-activity gene 2 (Rag2) knockout mouse, which preventstransplant rejection. In a syngeneic model, e.g. a syngeneic mousemodel, tumor tissues from the same genetic background as the givenimmuno-competent mouse strain are transplanted into the mouse to inducetumor formation. Optionally, cancer cells can be transformed with one ormore markers to facilitate analysis, for example, a Luciferase gene tomark PDX acute myeloid leukemia cells transplanted into an immunedeficient mouse via bone marrow engraftment. In some embodiments, theanimal model is an animal that has been genetically modified to containmutations that lead to cancer, for example by knocking out one or moregenes which suppress cancer formation, or introducing (knocking in) oneor more mutations that cause cancer, optionally in a tissue specificmanner using tissue specific drivers and recombination cassettes such asCre-LOX. For example, mice that are engineered to be p53+/−can be usedto study cancers as these animals spontaneously give rise to tumors inclones of cells that have lost the wild type p53 allele.

Alternatively, or in addition, the method of measuring activitycomprises measuring a change in RNA expression of certain genes intumor-derived cell cultures, blood, diseased tissues or diseased organsof treated individuals. The gene or genes can be, for example, genesthat are regulated by p300. p300 regulation of target genes can beeither direct (e.g. transcriptional regulation, through p300 activity atthe cognate gene promoter), or indirect (e.g., through p300 regulationof upstream transcription factors involved in regulation of a targetgene). Exemplary p300 target genes include, but are not limited to,androgen response genes such as kallikrein related peptidase3/prostate-specific antigen (KLK3/PSA), transmembrane serine protease 2(TMPRSS2) and solute carrier family 45 member 3 (SLC45A3), VEGF and P53.

Alternatively, or in addition, the method of measuring activitycomprises measuring the change in RNA expression of p300 target genes invitro in cell culture assays. Methods of measuring RNA expression ofp300 target genes will be readily apparent to one of ordinary skill inthe art. For example, levels of RNA expression can be measured usinghigh throughput sequencing methods, microarrays, reverse transcriptionpolymerase chain reaction (RT-PCR), quantitative RT-PCR (RT-qPCR) anddroplet digital PCR (ddPCR) as well as any other method known in theart. In some embodiments, the method of measuring activity comprisesmeasuring the change in RNA expression of Androgen Receptor—responsivegenes in vitro in cell culture assays (for example, KLK3, TMPRSS2 and/orSLC45A3). In some embodiments, the method of measuring activitycomprises measuring the amount of Tumor-specific Protein 53 (p5³) invitro in cell culture assays.

In some embodiments, the method of measuring activity comprisesmeasuring the amount of acetylated p53 lysine 382 (p53K382Ac) in vitroin cell culture assays. The amount of acetylated p53 lysine 382 can bemeasured, for example, by using a p53K382Ac specific antibody andWestern Blot.

In some embodiments, the method of measuring activity comprisesmeasuring the amount of Prostate-Specific Antigen protein in serum oftreated individuals. The amount of PSA can be measured, for example,with a PSA specific antibody and by Western Blot or ELISA.

In some embodiments, the method of measuring activity comprisesmeasuring the amount of Vascular Endothelial Growth Factor (VEGF)protein in serum, diseased tissues or diseased organs of treatedindividuals. The amount of VEGF protein can be measured, for example,with a VEGF specific antibody and by Western Blot or ELISA.Alternatively, or in addition, the method of measuring activitycomprises measuring the amount of VEGF RNA in serum, diseased tissues ordiseased organs of treated individuals.

Kits and Article of Manufacture

The disclosure provides kits comprising the compounds and pharmaceuticalcompositions of the disclosure and instructions for use in treating acancer in a subject in need thereof.

In some embodiments, the kits further comprise at least one additionalcancer therapeutic agent. Any additional cancer therapeutic describedherein is envisaged as being within the scope of a kit of thedisclosure. In some embodiments, the compounds or pharmaceuticalcompositions of the disclosure and the at least one additional cancertherapeutic are different compositions. In some embodiments, thecompounds or pharmaceutical compositions of the disclosure and the atleast one additional cancer therapeutic formulated in the samecomposition.

In some embodiments, the at least one additional cancer therapeuticagent comprises a chemotherapeutic agent. Exemplary chemotherapeuticagents include, but are not limited to a platinum compound, analkylating agent, an antitumor antibiotic, a taxane, an antimetabolite,a nucleoside analog, a topoisomerase inhibitor, a hypomethylating agent,a proteasome inhibitor, an epipodophyllotoxin, a DNA synthesisinhibitor, a vinca alkaloid, a tyrosine kinase inhibitor, a nitrosourea,hexamethylmelamine, mitotane, an angiogenesis inhibitor, a steroid, ahormonal agent, an aromatase inhibitor, arsenic trioxide, tretinoin, anonselective cyclooxygenase inhibitor, a selective cyclooxygenase-2(COX-2) inhibitors, or a combination thereof.

In some embodiments, the additional cancer therapeutic agent comprises abiological agent. Exemplary biological agents include, but are notlimited to, an antibody therapy, an adoptive cell therapy, an enzyme, acytokine, a growth factor or inhibitor thereof, a gene therapy a cancervaccine or a combination thereof.

In some embodiments, the additional cancer therapeutic agent comprisesan immune checkpoint inhibitor. The immune checkpoint inhibitor can be asmall molecule, or an antibody. Exemplary antibodies include, but arenot limited to, nivolumab, pembrolizumab, atezolizumab, avelumab,durvalumab or ipilimumab.

Kits comprising the compounds and pharmaceutical compositions of thedisclosure are for the use in treating a cancer in a subject. Exemplarycancers include liquid tumors such as leukemias and lymphomas, and solidtumors such as carcinomas, sarcomas, myelomas, germ cell tumors,carcinoid tumors, neuroendocrine tumors or tumors of mixed type.Exemplary cancers include, but are not limited to prostate cancer, coloncancer, head-and-neck cancer, cervical cancer, brain or nervous systemcancer, ovarian cancer, stomach or gastric cancer, kidney cancer, livercancer, oesophageal cancer, pancreatic cancer, skin cancer and lungcancer.

Articles of manufacture include, but are not limited to labels,instructional pamphlets, vials and syringes.

Enumerated Embodiments

The invention may be defined by reference to the following enumerated,illustrative embodiments:

1. A compound of formula (Ia)

or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein:

R¹ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by cycloalkyl,aryl or heteroaryl, wherein the cycloalkyl, aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R² is selected from H, C(O)R¹⁴, C(O)NR¹⁵R¹⁵, C(O)OR¹⁵, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₅alkyl-OR⁸, C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₅alkyl-NHCOR¹³, or C₁₋₃ alkyl substituted by cycloalkyl, aryl orheteroaryl, wherein the cycloalkyl, aryl or the heteroaryl is optionallysubstituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; with the provisothat when R² is C(O)NR¹⁵R¹⁵, both R¹⁵ can form a ring wherein the ringcontains the N of NR¹⁵R¹⁵ and optionally one further heteroatom selectedfrom O and N, wherein if the one further heteroatom is N, it isoptionally substituted by R⁸;

R³ and R⁷ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl, alloptionally substituted by halogen, OR⁸, NR⁸R¹¹, or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁴ is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by cycloalkyl,aryl or heteroaryl, wherein the cycloalkyl, aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁵ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, C₁₋₃ alkyl-OR⁸, or SR⁸; and whereinR⁵ can form a ring with any part of X or Y, wherein the ring optionallycontains a carbonyl group;

R⁶ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloakenyl, all optionally substituted by halogen,OR⁸, NR⁸R¹¹; C₁₋₃ alkyl substituted by C(O)NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; andwherein R⁶ can form a ring with any part of X; or is imidazolidinone;

R⁸ and R¹¹ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl;

X is selected from a bond, C₁₋₇ alkanediyl, C₂₋₇ alkenediyl, C₂₋₇alkynediyl, C₃₋₉ cycloalkanediyl, C₄₋₆ cycloalkenediyl, —O—, C₁₋₃alkanediyl-O—, —O—C₁₋₇ alkanediyl, —O—C₃₋₉ cycloalkanediyl, C₁₋₃alkanediyl-O—C₁₋₇ alkanediyl, C₁₋₇ heteroalkanediyl, or —S—C₁₋₇alkanediyl; and wherein X can form a ring or a polycyclic system withany part of R⁵, R⁶, or Y, wherein the ring optionally contains acarbonyl group;

Y is selected from H, C(O)NR¹⁰R¹², C(O)OR¹⁰, R¹¹NC(O)NR¹⁰R¹², OC(O)R¹⁰,OC(O)NR¹⁰R¹², S(O)_(n)R⁸ wherein n is 0, 1 or 2, SO₂NR¹⁰R¹², NR¹⁰SO₂R¹⁰,NR¹⁰R¹², HNCOR⁸, CN, C₃₋₇-cycloalkyl optionally containing a heteroatomin the ring selected from O and N wherein if the heteroatom is N it isoptionally substituted by R⁸; S-aryl, O-aryl, S-heteroaryl, O-heteroarylwherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionallysubstituted by one or more R⁹ or R¹⁴; or aryl, heteroaryl wherein thearyl or heteroaryl is optionally substituted by one or more of R⁸; andwherein Y can form a ring with any part of X or R⁵, wherein the ringoptionally contains a carbonyl group; with the proviso that when Y isC(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² can form a ring wherein the ringcontains the N of NR¹⁰R¹² and optionally one further heteroatom selectedfrom O and N, wherein if the one further heteroatom is N, it isoptionally substituted by R⁸;

R⁹ is selected from H, halogen, C₁₋₅ alkyl, C₂₋₅ alkenyl, C₂₋₅ alkynyl,C₃₋₅ cycloalkyl, C₁₋₅ alkyl-OR⁸, C₁₋₅ alkyl-SR⁸, C₁₋₅ alkyl-NR⁸R¹¹, C₁₋₅alkyl-C(O)OR⁸, C₁₋₅ alkyl-C(O)NR⁸R¹¹, C₁₋₅ alkyl-C(O)R¹⁰, CN, C(O)R⁸,C(O)NR⁸R¹¹, C(O)OR⁸, NR⁸C(O)NR⁸R¹¹, OC(O)NR⁸R¹¹, SO₂NR⁸R¹¹, NR⁸SO₂R⁸,OR⁸, NR⁸R¹¹, or S(O)_(n)R⁸ wherein n is 0, 1 or 2;

R¹⁰ and R¹² are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₃alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₃ alkyl-aryl, or C₁₋₃alkyl-heteroaryl, all these groups optionally substituted by halogen,OR⁸, or NR⁸R¹¹;

R¹³ is C₁₋₅ alkyl substituted by a bicyclic ring optionally containingat least one heteroatom and a carbonyl group;

R¹⁴ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; and

each R¹⁵ is independently selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, or C₁₋₃alkyl-OR⁸.

2. A compound of formula (I)

or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein:

R¹ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R² is selected from H, C(O)R¹⁴, C(O)NR¹⁵R¹⁵, C(O)OR¹⁵, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₅alkyl-OR⁸, C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₅alkyl-NHCOR¹³, or C₁₋₃ alkyl substituted by aryl or heteroaryl, whereinthe aryl or the heteroaryl is optionally substituted by halogen, C₁₋₄alkyl or C₃₋₅ cycloalkyl; with the proviso that when R² is C(O)NR¹⁵R¹⁵,both R¹⁵ can form a ring wherein the ring contains the N of NR¹⁵R¹⁵ andoptionally one further heteroatom selected from O and N, wherein if theone further heteroatom is N, it is optionally substituted by R⁸;

R³ and R⁷ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, alloptionally substituted by halogen, OR⁸, NR⁸R¹¹; or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁴ is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl;

R⁵ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, C₁₋₃ alkyl-OR⁸, or SR⁸; and whereinR⁵ can form a ring with any part of X or Y, wherein the ring optionallycontains a carbonyl group;

R⁶ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, all optionally substituted by halogen,OR⁸, NR⁸R¹¹; or C₁₋₃ alkyl substituted by C(O)NR⁸R¹¹; C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; or isimidazolidinone;

R⁸ and R¹¹ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl;

X is selected from a bond, C₁₋₇ alkanediyl, C₂₋₇ alkenediyl, C₂₋₇alkynediyl, C₃₋₆ cycloalkanediyl, C₄₋₆ cycloalkenediyl, —O—, C₁₋₃alkanediyl-O—, —O—C₁₋₇ alkanediyl, C₁₋₃ alkanediyl-O—C₁₋₇ alkanediyl,C₁₋₇ heteroalkanediyl, or —S—C₁₋₇ alkanediyl; and wherein X can form aring with any part of R⁵ or Y, wherein the ring optionally contains acarbonyl group;

Y is selected from H, C(O)NR¹⁰R¹², C(O)OR¹⁰, R¹¹NC(O)NR¹¹R¹², OC(O)R¹⁰,OC(O)NR¹⁰R¹², S(O)_(n)R⁸ wherein n is 0, 1 or 2, SO₂NR¹⁰R¹², NR¹⁰SO₂R¹⁰,NR¹⁰R¹², HNCOR⁸, CN, C₃₋₇-cycloalkyl optionally containing a heteroatomin the ring selected from O and N wherein if the heteroatom is N it isoptionally substituted by R⁸; S-aryl, O-aryl, S-heteroaryl, O-heteroarylwherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionallysubstituted by one or more R⁹ or R¹⁴; aryl, or heteroaryl wherein thearyl or heteroaryl is optionally substituted by one or more of R⁸; andwherein Y can form a ring with any part of X or R⁵, wherein the ringoptionally contains a carbonyl group; with the proviso that when Y isC(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² can form a ring wherein the ringcontains the N of NR¹⁰R¹² and optionally one further heteroatom selectedfrom O and N, wherein if the one further heteroatom is N, it isoptionally substituted by R⁸;

R⁹ is selected from H, halogen, C₁₋₅ alkyl, C₂₋₅ alkenyl, C₂₋₅ alkynyl,C₃₋₅ cycloalkyl, C₁₋₅ alkyl-OR⁸, C₁₋₅ alkyl-SR⁸, C₁₋₅ alkyl-NR⁸R¹¹, C₁₋₅alkyl-C(O)OR⁸, C₁₋₅ alkyl-C(O)NR⁸R¹¹, C₁₋₅ alkyl-C(O)R¹⁰, CN, C(O)R⁸,C(O)NR⁸R¹¹, C(O)OR⁸, NR⁸C(O)NR⁸R¹¹, OC(O)NR⁸R¹¹, SO₂NR⁸R¹¹, NR⁸SO₂R⁸,OR⁸, NR^(B)R¹¹, or S(O)_(n)R⁸ wherein n is 0, 1 or 2;

R¹⁰ and R¹² are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₃alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₃ alkyl-aryl, or C₁₋₃alkyl-heteroaryl, all these groups optionally substituted by halogen,OR⁸, or NR⁸R¹¹;

R¹³ is C₁₋₅ alkyl substituted by a bicyclic ring optionally containingat least one heteroatom and a carbonyl group;

R¹⁴ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; and

each R¹⁵ is independently selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, or C₁₋₃alkyl-OR⁸.

3. The compound according to any one of the previous embodiments,wherein R¹ is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl.4. The compound according to any one of the previous embodiments,wherein R¹ is selected from C₂₋₇ alkyl, C₃₋₇ cycloalkyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl.5. The compound according to any one of the previous embodiments,wherein R¹ is selected from C₃₋₇ alkyl, C₃₋₇ cycloalkyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl.6. The compound according to any one of the previous embodiments,wherein R² is selected from H, C(O)R¹⁴, C(O)OR¹⁵, C₁₋₇ alkyl, C₃₋₇cycloalkyl, C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₅alkyl-OR⁸, C₁₋₅ alkyl-NHCOR¹³, or C₁₋₃ alkyl substituted by aryl,wherein the aryl is optionally substituted by halogen, C₁₋₄ alkyl orC₃₋₅ cycloalkyl.7. The compound according to any one of the previous embodiments,wherein R² is selected from H, C(O)R¹⁴, wherein R¹⁴ is C₁₋₇ alkyl; C₁₋₇alkyl, C₃₋₇ cycloalkyl, C₁₋₅ alkyl-OR⁸, C₁₋₅ alkyl-NHCOR¹³, wherein R¹³is pentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3-one; orC₁₋₃ alkyl substituted by aryl, wherein the aryl is optionallysubstituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl.8. The compound according to any one of the previous embodiments,wherein R³ and R⁷ are each independently selected from H, C₁₋₇ alkyl,C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl.9. The compound according to any one of the previous embodiments,wherein R³ and R⁷ are H.10. The compound according to any one of the previous embodiments,wherein R⁴ is selected from C₁₋₇ alkyl, C₃₋₇ cycloalkyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl.11. The compound according to any one of the previous embodiments,wherein R⁴ is selected from C₂₋₇ alkyl, C₃₋₇ cycloalkyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃-s cycloalkyl.12. The compound according to any one of the previous embodiments,wherein R⁴ is selected from C₃₋₇ alkyl, C₃₋₇ cycloalkyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl.13. The compound according to any one of the previous embodiments,wherein the compound is of any one of Formulae (IIa), (IIb), or (IIc):

or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X, and Y are as describedherein.14. The compound according to any one of the previous embodiments,wherein the compound is of any one of Formulae (IIIa), (IIIb), (IIIc),or (IIId):

or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein R¹, R⁴, R⁵, R⁶, X, and Y are as described herein.15. The compound according to any one of the previous embodiments,wherein R⁵ is selected from H, C₁₋₇ alkyl, OR⁸, or SR⁸; and wherein C₁₋₇alkyl, OR⁸ or SR⁸ of R⁵ can form a ring with any part of X or Y, whereinthe ring optionally contains a carbonyl group.16. The compound according to any one of the previous embodiments,wherein R⁶ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl,C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl; or is imidazolidinone.17. The compound according to any one of the previous embodiments,wherein R⁶ is H, C₁₋₇ alkyl, or imidazolidinone.18. The compound according to any one of the previous embodiments,wherein the compound is of any one of Formulae (IVa), (IVb), (IVc) or(IVd):

or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein R¹, R², R⁴, R⁵, R⁶, X, and Y are as described herein.19. The compound according to any one of the previous embodiments,wherein R⁸ and R¹¹ are each independently selected from H, C₁₋₇ alkyl,C₂₋₇ alkenyl, or C₃₋₇ cycloalkyl.20. The compound according to any one of the previous embodiments,wherein R⁹ is selected from H, C₁₋₅ alkyl, halogen, C₁₋₅ alkyl-NR⁸R¹¹,C₁₋₅ alkyl-C(O)OR⁸, C₁₋₅ alkyl-C(O)NR⁸R¹¹, CN, C(O)R⁸, C(O)NR⁸R¹¹,C(O)OR⁸, or OR⁸.21. The compound according to any one of the previous embodiments,wherein R¹⁰ and R¹² are each independently selected from H, C₁₋₇ alkyl,C₂₋₇ alkenyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₃ alkanediyl-O—C₁₋₃alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₃ alkyl-aryl, or C₁₋₃ alkyl-heteroaryl,all these groups optionally substituted by halogen or OR⁸.22. The compound according to any one of the previous embodiments,wherein R¹⁴ is selected from C₁₋₇ alkyl, C₃₋₇ cycloalkyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl.23. The compound according to any one of the previous embodiments,wherein R¹⁴ is selected from C₁₋₇ alkyl or C₃₋₇ cycloalkyl.24. The compound according to any one of the previous embodiments,wherein R¹⁴ is C₁₋₇ alkyl.25. The compound according to any one of the previous embodiments,wherein each R¹⁵ is independently selected from H, C₁₋₇ alkyl, or C₃₋₇cycloalkyl.26. The compound according to any one of the previous embodiments,wherein each R¹⁵ is independently selected from H, C₁₋₇ alkyl.27. The compound according to any one of the previous embodiments,wherein X is selected from a bond, C₁₋₇ alkanediyl, —O—, C₁₋₃alkanediyl-O—, —O—C₁₋₇ alkanediyl, C₁₋₃ alkanediyl-O—C₁₋₇ alkanediyl,C₁₋₇ heteroalkanediyl, or —S—C₁₋₇ alkanediyl; and wherein X can form aring with any part of R⁵ or Y, wherein the ring optionally contains acarbonyl group.28. The compound according to any one of the previous embodiments,wherein X is selected from a bond and C₁₋₇ alkanediyl, and wherein C₁₋₇alkanediyl of X can form a ring with any part of Y.29. The compound according to any one of the previous embodiments,wherein X is selected from a bond, —O—C₁₋₇ alkanediyl, —S—C₁₋₇alkanediyl and C₁₋₇ alkanediyl, and wherein —O—C₁₋₇ alkanediyl, —S—C₁₋₇alkanediyl or C₁₋₇ alkanediyl of X can form a ring with any part of R⁵,wherein the ring optionally contains a carbonyl group.30. The compound according to any one of the previous embodiments,wherein Y is selected from H, C(O)NR¹⁰R¹², C(O)OR¹⁰, NR¹⁰R¹², CN,C₃₋₇-cycloalkyl optionally containing a heteroatom in the ring selectedfrom O and N wherein if the heteroatom is N it is optionally substitutedby R⁸; S-aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl,O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one ormore R⁹ or R¹⁴; or aryl, heteroaryl wherein the aryl or heteroaryl isoptionally substituted by one or more of R⁸; and wherein when Y isC(O)NR¹R¹² or NR¹⁰R¹², Y can form a ring with any part of X or R⁵,wherein the ring optionally contains a carbonyl group; with the provisothat when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² can form a ringwherein the ring contains the N of NR¹⁰R¹² and optionally one furtherheteroatom selected from O and N, wherein if the one further heteroatomis N, it is optionally substituted by R⁸.31. The compound according to any one of the previous embodiments,wherein Y is selected from H, C(O)NR¹⁰R¹², C(O)OR¹⁰, NR¹⁰R¹², CN,C₃₋₇-cycloalkyl optionally containing a heteroatom in the ring selectedfrom O and N wherein if the heteroatom is N it is optionally substitutedby R⁸; S-aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl,O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one ormore R⁹ or R¹⁴; or aryl, heteroaryl wherein the aryl or heteroaryl isoptionally substituted by one or more of R⁸; and wherein Y can form aring with any part of X or R⁵, wherein the ring optionally contains acarbonyl group; with the proviso that when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹²,R¹⁰ and R¹² can form a ring wherein the ring contains the N of NR¹⁰R¹²and optionally one further heteroatom selected from O and N, wherein ifthe one further heteroatom is N, it is optionally substituted by R⁸.32. The compound according to any one of the previous embodiments,wherein Y is selected from C(O)NR¹⁰R¹², NR¹⁰R¹², C₃₋₇-cycloalkyloptionally containing a heteroatom in the ring selected from O and Nwherein if the heteroatom is N it is optionally substituted by R⁸;S-aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl, O-aryl,S-heteroaryl, O-heteroaryl are optionally substituted by one or more R⁹or R¹⁴; or heteroaryl wherein the heteroaryl is optionally substitutedby one or more of R⁸; and wherein Y can form a ring with any part of Xor R⁵, wherein the ring optionally contains a carbonyl group; with theproviso that when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² can form aring wherein the ring contains the N of NR¹⁰R¹² and optionally onefurther heteroatom selected from O and N, wherein if the one furtherheteroatom is N, it is optionally substituted by R⁸.33. The compound according to any one of the previous embodiments,wherein the compound is of any one of Formulae (Va), (Vb), (Vc), or(Vd):

or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3,and R¹, R², R³, R⁴, R⁶, R⁷, R¹⁰ and R¹² are as described herein.34. The compound according to any one of the previous embodiments,wherein the compound is of any one of Formulae (VIa), (VIb), (VIc), or(VId):

or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3,and R¹, R², R³, R⁴, R⁶, R⁷, R¹⁰ and R¹² are as described herein.35. The compound according to any one of the previous embodiments,wherein Y is selected from NR¹⁰R¹² and C₃₋₇-cycloalkyl optionallycontaining a heteroatom in the ring selected from O and N wherein if theheteroatom is N it is optionally substituted by R⁸; and wherein Y canform a ring with any part of X or R⁵; with the proviso that when Y isNR¹⁰R¹², R¹⁰ and R¹² can form a ring wherein the ring contains the N ofNR¹⁰R¹² and optionally one further heteroatom selected from O and N,wherein if the one further heteroatom is N, it is optionally substitutedby R⁸.36. The compound according to any one of the previous embodiments,wherein R⁵ is selected from H and C₁₋₇ alkyl; wherein C₁₋₇ alkyl of R⁵can form a ring with any part of Y;wherein X is selected from a bond and C₁₋₇ alkanediyl, and wherein C₁₋₇alkanediyl of X can form a ring with any part of Y;wherein Y is selected from NR¹⁰R¹² and C₃₋₇-cycloalkyl optionallycontaining a heteroatom in the ring wherein the heteroatom is N and isoptionally substituted by R⁸ wherein R⁸ is C₁₋₇ alkyl;wherein Y can form a ring with any part of C₁₋₇ alkanediyl of X or withany part of C₁₋₇ alkyl of R⁵; with the proviso that when Y is NR¹⁰R¹²,R¹⁰ and R¹² can form a ring wherein the ring contains the N of NR¹⁰R¹²and optionally one further heteroatom selected from O and N, wherein ifthe one further heteroatom is N, it is optionally substituted by R⁸; andwherein R¹⁰ and R¹² are each independently selected from H, C₁₋₇ alkyl,C₃₋₇ cycloalkyl, C₁₋₃ alkyl-aryl, all these groups optionallysubstituted by halogen.37. The compound according to any one of the previous embodiments,wherein R⁵ is selected from C₁₋₇ alkyl, OR⁸, or SR⁸; wherein C₁₋₇ alkyl,OR⁸ or SR⁸ of R⁵ can form a ring with any part of X;wherein X is selected from —O—C₁₋₇ alkanediyl, —S—C₁₋₇ alkanediyl, orC₁₋₇ alkanediyl, and wherein —O—C₁₋₇ alkanediyl, —S—C₁₋₇ alkanediyl orC₁₋₇ alkanediyl of X can form a ring with any part of R⁵; andwherein Y is NR¹⁰R¹² wherein R¹⁰ and R¹² can form a ring wherein thering contains the N of NR¹⁰R¹² and optionally one further heteroatomselected from O and N, wherein if the one further heteroatom is N, it isoptionally substituted by R⁸.38. The compound according to any one of the previous embodiments,wherein R⁵ is OR⁸, wherein R⁸ of OR⁸ is C₁₋₇ alkyl, and wherein OR⁸ ofR⁵ can form a ring with any part of X;wherein X is —O—C₁₋₇ alkanediyl and wherein —O—C₁₋₇ alkanediyl of X canform a ring with any part of R⁵; andwherein Y is NR¹⁰R¹² wherein R¹⁰ and R¹² can form a ring wherein thering contains the N of NR¹⁰R¹² and four or five carbon atoms.39. The compound according to any one of the previous embodiments,wherein the compound is of any one of Formulae (VIIa), (VIIb), (VIIc),(VIId), (VIIe), or (VIIf):

or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein n8 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3,and R¹, R², R³, R⁴, R⁶, R⁷, and R⁸ are as described herein.40. The compound according to any one of the previous embodiments,wherein Y is aryl or heteroaryl, wherein the aryl or heteroaryl isoptionally substituted by one or more of R⁸; or S-heteroaryl, whereinthe S-heteroaryl is optionally substituted by one or more R¹⁴41. The compound according to any one of the previous embodiments,wherein R⁵ is selected from H and C₁₋₇ alkyl;wherein X is selected from a bond and C₁₋₇ alkanediyl;wherein Y is heteroaryl, wherein the heteroaryl is optionallysubstituted by one or more of R⁸; or S-heteroaryl, wherein theS-heteroaryl is optionally substituted by one or more R¹⁴.42. The compound according to any one of the previous embodiments,wherein Y is C(O)NR¹⁰R¹²; and wherein R¹⁰ and R¹² can form a ringwherein the ring contains the N of NR¹⁰R¹² and optionally one furtherheteroatom selected from O and N, wherein if the one further heteroatomis N, it is optionally substituted by R⁸.43. The compound according to any one of the previous embodiments,wherein R⁵ is selected from H and C₁₋₇ alkyl;wherein X is selected from a bond and C₁₋₇ alkanediyl;wherein Y is C(O)NR¹⁰R¹²; and wherein R¹⁰ and R¹² can form a ringwherein the ring contains the N of NR¹⁰R¹² and optionally one furtherheteroatom selected from O and N, wherein if the one further heteroatomis N, it is optionally substituted by R⁸; and wherein R¹⁰ and R¹² areeach independently selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₃₋₇cycloalkyl, C₁₋₃ alkyl-aryl.44. The compound according to any one of the previous embodiments,wherein Y is selected from S-aryl, O-aryl, S-heteroaryl, O-heteroaryl,wherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionallysubstituted by one or more R⁹ or R¹⁴45. The compound according to any one of the previous embodiments,wherein R⁵ is selected from H and C₁₋₇ alkyl;wherein X is selected from a bond and C₁₋₇ alkanediyl,wherein Y is selected from O-aryl and O-heteroaryl, wherein the O-arylor O-heteroaryl is optionally substituted by one or more R⁹;wherein R⁹ is selected from H, C₁₋₅ alkyl, halogen, C₁₋₅ alkyl-NR⁸R¹¹,C₁₋₅ alkyl-C(O)OR⁸, C₁₋₅ alkyl-C(O)NR⁸R¹¹, CN, C(O)R⁸, C(O)NR⁸R¹¹,C(O)OR⁸, and OR⁸.46. The compound according to any one of the previous embodiments,wherein Y is C(O)OR¹⁰.47. The compound according to any one of the previous embodiments,whereinwherein R⁵ is selected from H and C₁₋₇ alkyl;wherein X is selected from a bond and C₁₋₇ alkanediyl;wherein Y is C(O)OR¹⁰; andwherein R¹⁰ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃alkanediyl, C₁₋₃ alkyl-aryl, or C₁₋₃ alkyl-heteroaryl, all these groupsoptionally substituted by OR₈.48. The compound according to any one of the previous embodiments,wherein Y is H.49. The compound according to any one of the previous embodiments,whereinwherein R⁵ is C₁₋₇ alkyl;wherein X is a bond; andwherein Y is H.50. The compound according to any one of the previous embodiments,wherein Y is CN.51. The compound according to any one of the previous embodiments,wherein

R⁵ is H;

X is C₁₋₇ alkanediyl; and

Y is CN.

52. The compound according to any one of the previous embodiments,wherein the compound is of any one of Formulae (VIIIa), (VIIIb),(VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VIIIi), (VIIIj),(VIIIk), (VIIIl):

or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomerthereof, wherein Q₁ and Q₂ are each independently O, S, NR⁸, or CR⁸, andR¹, R², R³, R⁴, R⁶, R⁷, R⁸, and Y are as described herein.53. The compound according to any one of the previous embodiments,wherein the compound is of any one of Formulae (IXa), (IXb), (IXc), or(IXd):

or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomerthereof, wherein nl0 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or3, and R¹, R², R³, R⁴, R⁶, R⁷, R¹⁰, R¹² and Y are as described herein.54. A compound selected from the group consisting of:

55. A compound selected from the group consisting of:

56. The compound according to any one of the previous embodiments,wherein the compound is selected from a compound of any one of Table 2or Table 3.57. A pharmaceutical composition comprising a compound according to anyone of the previous embodiments and a pharmaceutically acceptablediluent, excipient or carrier.58. The pharmaceutical composition according to embodiment 57, furthercomprising an additional pharmaceutically active agent.59. The pharmaceutical composition according to embodiment 58, whereinthe additional pharmaceutically active agent comprises an additionalcancer therapy.60. The compound according to any one of embodiments 1-56 or thepharmaceutical composition according to embodiment 57 or 58 for use as amedicament.61. The compound according to any one of embodiments 1-56 or the or thepharmaceutical composition according to embodiment 57 or 58 for use in amethod for preventing or treating cancer in a subject in need thereof.62. The compound according to any one of embodiments 1-56 or thepharmaceutical composition according to embodiment 57 or 58 for the usein the manufacture of a medicament for the treatment of cancer in asubject in need thereof.63. A method of treating cancer in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acomposition comprising the compound of any one of embodiments 1-56 orthe pharmaceutical composition of embodiment 57 or 58.64. The method or composition for use according to any one ofembodiments 61-63, wherein the cancer comprises a solid tumor or aliquid tumor.65. The method or composition for use according to embodiment 64,wherein the solid tumor is a primary tumor or a metastatic tumor.66. The method or composition for use according to embodiment 64,wherein the solid tumor is a carcinoma, a sarcoma, a myeloma, a germcell tumor, a carcinoid tumor, a neuroendocrine tumor or a tumor ofmixed type.67. The method or composition for use according to embodiment 64,wherein the cancer comprises a lymphoma, a leukemia, a brain cancer, anervous system cancer, a breast cancer, a cervical cancer, an ovariancancer, a colorectal cancer, a stomach cancer, a gastric cancer, akidney cancer, a liver cancer, a lung cancer, an oesophageal cancer, apancreatic cancer, a prostate cancer, a colon cancer, a skin cancer or ahead-and-neck cancer.68. The method or composition for use according to embodiment 64,wherein the liquid tumor is a leukemia or a lymphoma.69. The method of composition for use according to any one ofembodiments 61-66, wherein the cancer is Stage I, Stage IIA, Stage IIB,Stage IIIA, Stage IIIB, Stage IIIC, or Stage IV cancer.70. The method or composition for use according to any one ofembodiments 61-69, wherein the subject is a mouse, a rat, a rabbit, anon-human primate or a human.71. The method or composition for use according to embodiment 70,wherein the human is a child, an adolescent or an adult.72. The method of composition for use according to any one ofembodiments 61-71, wherein the compound or pharmaceutical composition issuitable for oral administration.73. The method of composition for use according to any one ofembodiments 61-71, wherein the compound or pharmaceutical composition issuitable for parenteral administration.74. The method or composition for use according to embodiment 73,wherein the parenteral administration comprises subcutaneousadministration, intravenous injection, intravenous infusion,intraperitoneal injection, intramuscular injection or intratumoralinjection.75. The method or composition for use according to any one ofembodiments 61-74, wherein the method or use of the composition furthercomprises at least one additional cancer therapy.76. The method or composition for use according to embodiment 75,wherein the at least one additional cancer therapy comprises a standardof care for the cancer.77. The method or composition for use according to embodiment 75 or 76,wherein the at least one additional cancer therapy comprises surgicalresection of the cancer, radiation therapy, or a combination thereof.78. The method or composition for use according to embodiment 75,wherein the at least one additional cancer therapy comprisesadministration of at least one additional cancer therapeutic agent.79. The method or composition for use according to embodiment 78,wherein the administration comprises simultaneous administration of thecompound or pharmaceutical composition and the at least one additionalcancer therapeutic agent.80. The method or composition for use according to embodiment 79,wherein the compound or pharmaceutical composition and the at least oneadditional cancer therapeutic agent are in the same composition.81. The method or composition for use according to embodiment 78,wherein the administration comprises administration in temporalproximity of the compound or pharmaceutical composition and the at leastone additional cancer therapeutic agent.82. The method or composition for use according to embodiment 78,wherein the administration comprises sequential administration of thecompound or pharmaceutical composition and the at least one additionalcancer therapeutic agent.83. The method or composition for use according to any one ofembodiments 78-82, wherein the at least one additional cancertherapeutic agent comprises a chemotherapeutic agent.84. The method or composition for use according to embodiment 83,wherein the chemotherapeutic agent comprises a platinum compound, analkylating agent, an antitumor antibiotic, a taxane, an antimetabolite,a nucleoside analog, a topoisomerase inhibitor, a hypomethylating agent,a proteasome inhibitor, an epipodophyllotoxin, a DNA synthesisinhibitor, a vinca alkaloid, a tyrosine kinase inhibitor, a nitrosourea,hexamethylmelamine, mitotane, an angiogenesis inhibitor, a steroid, ahormonal agent, an aromatase inhibitor, arsenic trioxide, tretinoin, anonselective cyclooxygenase inhibitor, a selective cyclooxygenase-2(COX-2) inhibitors, or a combination thereof.85. The method or composition for use according to any one ofembodiments 78-82, wherein the at least one additional cancertherapeutic agent comprises a biological agent.86. The method or composition for use according to embodiment 85,wherein the biological agent comprises an antibody therapy, an adoptivecell therapy, an enzyme, a cytokine, a growth factor, an inhibitor of agrowth factor, a gene therapy a cancer vaccine or a combination thereof.87. The method or composition for use according to embodiment 86,wherein the antibody therapy comprises ituximab, cetuximab,obinutuzumab, ofatumumab, ibritumomab, brentuximab, bevacizumab,panitumumab, pembrolizumab, tositumomab, trastuzumab, alemtuzumab,gemtuzumab ozogamicin, bevacizumab, catumaxomab, denosumab,obinutuzumab, ofatumumab, ramucirumab, pertuzumab, ipilimumab,nivolumab, nimotuzumab, lambrolizumab, pidilizumab, siltuximab,tremelimumab.88. The method or composition for use according to embodiment 86,wherein the adoptive cell therapy comprises a chimeric antigen receptorT cell (CAR-T) therapy.89. The method or composition for use according to embodiment 88,wherein the adoptive cell therapy is autologous or allogeneic.90. The method or composition for use according to any one ofembodiments 78-82, wherein the at least one additional cancertherapeutic agent comprises an immune checkpoint inhibitor.91. The method or composition for use according to embodiment 90,wherein the immune checkpoint inhibitor comprises nivolumab,pembrolizumab, atezolizumab, avelumab, durvalumab or ipilimumab.92. The method or composition for use according to embodiment 86,wherein the antibody therapy comprises a VEGFA antibody.93. The method or composition for use according to embodiment 92,wherein the VEGFA antibody comprises bevacizumab (Avastin®).94. The method or composition for use according to any one ofembodiments 61-93, wherein the method or use of the compositionalleviates a sign or a symptom of the cancer.95. The method or composition for use according to embodiment 94,wherein alleviating a sign or a symptom of the cancer comprises areduction in tumor volume, a reduction in tumor size, a reduction intumor number, a decrease in the rate of growth of a tumor or acombination thereof.96. A kit, comprising the compound according to any one of embodiments1-56 or the pharmaceutical composition according to embodiment 57 or 58and instructions for use in treating cancer in a subject in needthereof.97. The kit according to embodiment 96, further comprising at least oneadditional cancer therapeutic agent.98. The kit according to embodiment 97, wherein the at least oneadditional cancer therapeutic agent comprises a chemotherapeutic agent.99. The kit according to embodiment 98, wherein the chemotherapeuticagent comprises a platinum compound, an alkylating agent, an antitumorantibiotic, a taxane, an antimetabolite, a nucleoside analog, atopoisomerase inhibitor, a hypomethylating agent, a proteasomeinhibitor, an epipodophyllotoxin, a DNA synthesis inhibitor, a vincaalkaloid, a tyrosine kinase inhibitor, a nitrosourea,hexamethylmelamine, mitotane, an angiogenesis inhibitor, a steroid, ahormonal agent, an aromatase inhibitor, arsenic trioxide, tretinoin, anonselective cyclooxygenase inhibitor, a selective cyclooxygenase-2(COX-2) inhibitors, or a combination thereof.100. The kit of embodiment according to embodiment 97, wherein the atleast one additional cancer therapeutic agent comprises a biologicalagent.101. The kit according to embodiment 100, wherein biological agentcomprises an antibody therapy, an adoptive cell therapy, an enzyme, acytokine, a growth factor, an inhibitor of a growth factor, a genetherapy a cancer vaccine or a combination thereof.102. The kit according to embodiment 97, wherein the at least oneadditional cancer therapeutic agent comprises an immune checkpointinhibitor.103. The kit according to embodiment 102, wherein the immune checkpointinhibitor comprises nivolumab, pembrolizumab, atezolizumab, avelumab,durvalumab or ipilimumab.

EXAMPLES

Abbreviations used in the following examples and elsewhere herein are:

DCC: dicyclohexylcarbodiimideDCM: dichloromethaneDMF: dimethylformamideDMP: Dess-Martin periodinane;1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-oneDMSO: dimethylsulfoxideHATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphateMS−: mass spectrumNMP: N-methyl-2-pyrrolidoneNMR: nuclear magnetic resonanceNosyl: 2-nitrosulfonylTBDMS−: t-butyldimethylsilyltBOC or BOC: t-butyloxycarbonylTFA: trifluoroacetic acidTHF: tetrahydrofuranTHP: 2-tetrahydropyranyl

The compounds have been prepared in accordance to the followingschemes/methods. However, other methods are known for the synthesis.

Synthesis of I,(S)-2-[(S)-3-isobutyl-4-(o-nitrophenylsulfonyl)-2-oxo-1-piperazinyl]-4-methylvalericAcid According to Synthetic Method C (Scheme 3) Synthesis of Ia(S)-4-methyl-2-(o-nitrophenylsulfonylamino)valeric Acid

To a solution of L-leucine (1 eq.) and N,N-diisopropylethylamine (3.2eq.) in a water/THF solvent mixture cooled at 0° C. is addedo-(chlorosulfonyl)nitrobenzene (1.3 eq.). The solution is allowed towarm up to room temperature and stirred overnight. The residue isacidified, extracted and concentrated to yield the title compound as anorange solid.

¹H NMR (300 MHz, CD₃OD), δ (ppm): 8.16-8.03 (m, 1H), 7.90-7.73 (m, 3H),4.07 (dd, 1H), 1.88-1.72 (m, 1H), 1.66-1.51 (m, 2H), 0.94 (d, 3H), 0.88(d, 3H)

MS⁻: 315 (M−H)

Synthesis of methyl(S)-2-[(S)-4-methyl-2-(o-nitrophenylsulfonylamino)valerylamino]-4-methylvalerate

To a solution of Ia ((S)-4-methyl-2-(o-nitrophenylsulfonylamino)valericacid) (1 eq.), Ib (methyl (S)-2-amino-4-methylvalerate hydrochloride)(1.1 eq.) and N,N-diisopropylethylamine (3 eq.) in DMF is added HATUreagent (1.1 eq.). The solution is stirred at room temperatureovernight. After aqueous work-up, the organic residue is concentratedand re-crystallized to yield the title compound as a colourless solid.

¹H NMR (300 MHz, CDCl₃), δ (ppm): 8.14-8.09 (m, 1H), 7.94-7.88 (m, 1H),7.78-7.70 (m, 2H), 6.48 (d, 1H), 6.15 (d, 1H), 4.45-4.35 (m, 1H),4.06-3.97 (m, 1H), 3.68 (s, 3H), 1.80-1.37 (m, 8H), 0.90-0.85 (m, 6H),0.82-0.78 (m, 6H)

MS⁻: 442 (M−H)

Synthesis of methyl(S)-2-[(S)-3-isobutyl-4-(o-nitrophenylsulfonyl)-2-oxo-1-piperazinyl]-4-methylvalerate

To a solution of methyl (S)-2-[(S)-4-methyl-2-(o-nitrophenylsulfonylamino)valerylamino]-4-methylvalerate (1 eq.) and Ic(1,2-dibromoethane) (4 eq.) in DMF is added potassium carbonate (4 eq.).The mixture is stirred at 65° C. overnight. After aqueous work-up, theorganic residue is purified by flash chromatography to yield the titlecompound as an orange solid.

¹H NMR (300 MHz, CDCl₃), δ (ppm): 8.06-8.02 (m, 1H), 7.78-7.66 (m, 3H),5.09 (dd, 1H), 4.53 (dd, 1H), 4.07-3.98 (m, 1H), 3.65-3.55 (m, 1H), 3.58(s, 3H), 3.45-3.36 (m, 1H), 3.18-3.10 (m, 1H), 1.77-1.61 (m, 5H),1.41-1.24 (m, 1H), 0.96-0.85 (m, 12H)

MS⁺: 470 (M+H)

Synthesis of I,(S)-2-[(S)-3-isobutyl-4-(o-nitrophenylsulfonyl)-2-oxo-1-piperazinyl]-4-methylvalericAcid

To a solution of methyl(S)-2-[(S)-3-isobutyl-4-(o-nitrophenylsulfonyl)-2-oxo-1-piperazinyl]-4-methylvalerate(1 eq.) in methanol is added a solution of lithium hydroxide (1.5 eq.)in water. The mixture is stirred at room temperature for 2 h thenconcentrated. The residue is acidified, extracted and concentrated to agum that is re-crystallized to yield the title compound as a colourlesssolid.

¹H NMR (300 MHz, CDCl₃), δ (ppm): 8.85-7.85 (br s, 1H), 8.06-8.01 (m,1H), 7.78-7.63 (m, 3H), 5.09 (dd, 1H), 4.59 (m, 1H), 4.14-4.05 (m, 1H),3.65-3.54 (m, 1H), 3.45-3.33 (m, 1H), 3.17-3.09 (m, 1H), 1.78-1.61 (m,5H), 1.45-1.30 (m, 1H), 0.97-0.87 (m, 12H)

MS⁻: 454 (M−H)

Synthesis of(S)-1-[(S)-1-({4-[(1-cyclopropyl-1H-imidazol-2-yl)methyl]-1-piperidyl}carbonyl)-3-methylbutyl]-3-isobutyl-2-piperazinoneFollowing Synthetic Method A (Scheme 1) Synthesis of II Synthesis oftert-butyl 4-(2-hydroxyethyl)-1-piperidinecarboxylate

To a solution of 2-(4-piperidyl)ethanol (1 eq.) in a mixture THF/wateris added di-tert-butyl dicarbonate (1.3 eq.) and sodium bicarbonate (2eq.). The mixture is stirred at room temperature overnight. Afteraqueous work-up, the residue is purified by flash chromatography toyield the title compound as a light yellow oil.

¹H NMR (300 MHz, CDCl₃), δ (ppm): 4.08 (br d, 2H), 3.71 (t, 2H), 2.70(br t, 2H), 1.73-1.47 (m, 6H), 1.46 (s, 9H), 1.21-1.04 (m, 2H)

Synthesis of tert-butyl 4-(formylmethyl)-1-piperidinecarboxylate

To a solution of tert-butyl 4-(2-hydroxyethyl)-1-piperidinecarboxylate(1 eq.) in DCM is added DMP (2 eq.). The mixture is stirred at roomtemperature overnight. After aqueous work-up, the residue is purified byflash chromatography to yield the title compound as a yellow oil.

¹H NMR (300 MHz, CDCl₃), δ (ppm): 9.78 (br s, 1H), 4.08 (br d, 2H), 2.74(br t, 2H), 2.39 (d, 2H), 2.12-1.89 (m, 1H), 1.79-1.64 (m, 2H), 1.45 (s,9H), 1.26-1.10 (m, 2H)

Synthesis of tert-butyl4-[(1-cyclopropyl-1H-imidazol-2-yl)methyl]-1-piperidinecarboxylate

To a solution of tert-butyl 4-(formylmethyl)-1-piperidinecarboxylate (1eq.) and glyoxal (1.2 eq.) in methanol is added cyclopropylamine (2 eq.)and ammonium acetate (1 eq.). The mixture is stirred at room temperatureovernight then concentrated. The residue is purified by flashchromatography to yield the title compound as a yellow oil.

¹H NMR (300 MHz, CDCl₃), δ (ppm): 6.89 (s, 1H), 6.75 (s, 1H), 4.12-3.93(m, 2H), 3.16-3.07 (m, 1H), 2.77-2.58 (m, 4H), 1.72-1.57 (m, 2H), 1.40(s, 9H), 1.22-0.86 (m, 7H)

Synthesis of II, 1-cyclopropyl-2-[(4-piperidyl)methyl]-1H-imidazole

To a cooled solution of tert-butyl4-[(1-cyclopropyl-1H-imidazol-2-yl)methyl]-1-piperidinecarboxylate inDCM is added TFA. The solution is stirred at room temperature for 1 hthen concentrated and the residue is neutralized with sodium hydroxideto yield the title compound as a yellow gum.

¹H NMR (300 MHz, CD₃OD), δ (ppm): 7.06 (s, 1H), 6.91 (s, 1H), 3.27-3.20(m, 2H), 2.95-2.79 (m, 4H), 2.20-2.05 (m, 1H), 1.86-1.73 (m, 2H),1.56-1.25 (m, 3H), 1.08-0.99 (m, 2H), 0.94-0.86 (m, 2H)

Synthesis of(S)-1-[(S)-1-({4-[(1-cyclopropyl-1H-imidazol-2-yl)methyl]-1-piperidyl}carbonyl)-3-methylbutyl]-3-isobutyl-4-(o-nitrophenylsulfonyl)-2-piperazinone

To a cooled solution of I (vide supra) (1 eq.) and II(1-cyclopropyl-2-[(4-piperidyl)methyl]-1H-imidazole) (1 eq.) in DMF isadded HATU reagent (2 eq.). The solution is stirred at room temperatureovernight. After an aqueous work-up, the organic residue is purified byflash chromatography to yield the title compound as a yellow oil.

¹H NMR (300 MHz, CDCl₃), δ (ppm): 8.12-8.04 (m, 1H), 7.84-7.64 (m, 3H),7.07-6.90 (m, 2H), 5.62 (t, 0.55H), 5.48 (t, 0.45H), 4.54-4.33 (m, 2H),4.24-4.14 (m, 0.5H), 4.03-3.84 (m, 1.5H), 3.57-3.43 (m, 1H), 3.40-3.00(m, 4H), 2.86-2.78 (m, 1.5H), 2.71-2.33 (m, 1.5H), 2.27-2.04 (m, 1H),1.79-1.30 (m, 9H), 1.21-1.10 (m, 2H), 1.05-0.95 (m, 2H), 0.95-0.83 (m,12H), 0.83-0.76 (m, 2H)

MS⁺: 643 (M+H)

Synthesis of(S)-1-[(S)-1-({4-[(1-cyclopropyl-1H-imidazol-2-yl)methyl]-1-piperidyl}carbonyl)-3-methylbutyl]-3-isobutyl-2-piperazinone

A mixture of(S)-1-[(S)-1-({4-[(1-cyclopropyl-1H-imidazol-2-yl)methyl]-1-piperidyl}carbonyl)-3-methylbutyl]-3-isobutyl-4-(o-nitrophenylsulfonyl)-2-piperazinone(1 eq.), 2-mercaptoethanol (2 eq.) and cesium carbonate (3 eq.) in DMFis stirred at room temperature for 2 h. After filtration, concentrationand flash chromatography purification, the title compound is obtained asa colourless oil.

¹H NMR (300 MHz, CD₃OD), δ (ppm): 6.98 (s, 1H), 6.82 (s, 1H), 5.63-5.52(m, 1H), 4.58-4.42 (m, 1H), 4.19-3.99 (m, 1H), 3.48-3.40 (m, 1H),3.38-3.27 (m, 2H), 3.19-3.03 (m, 2H), 2.98-2.85 (m, 1H), 2.80 (d, 2H),2.77-2.61 (m, 1H), 2.27-2.09 (m, 1H), 1.90-1.43 (m, 8H), 1.30-1.06 (m,4H), 1.04-0.86 (m, 15H)

MS⁺: 458 (M+H), 480 (M+Na)

Synthesis of(S)-1-[(S)-3-methyl-1-({4-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-1-piperidyl}carbonyl)butyl]-3-isobutyl-2-piperazinoneFollowing Synthetic Method B (Scheme 2) Synthesis of III (methyl(1-{(S)-2-[(S)-3-isobutyl-4-(o-nitrophenylsulfonyl)-2-oxo-1-piperazinyl]-4-methylvaleryl}-4-piperidyl)acetate)by Method B1

HATU reagent (1.5 eq.) is added to a cooled solution of IIIa((S)-2-[(S)-3-isobutyl-4-(o-nitrophenylsulfonyl)-2-oxo-1-piperazinyl]-4-methylvalericacid, vide supra) (1 eq.) and IIIb (methyl (4-piperidyl)acetate) (2 eq.)in DMF. The solution is stirred at room temperature overnight. After anaqueous work-up, the organic residue is purified by flash chromatographyto yield the title compound as a light yellow solid.

¹H NMR (300 MHz, CDCl₃), δ (ppm): 8.13-8.05 (m, 1H), 7.81-7.67 (m, 3H),5.65-5.57 (m, 0.5H), 5.54-5.46 (m, 0.5H), 4.52-4.39 (m, 2H), 4.21-4.12(m, 0.5H), 4.00-3.86 (m, 1.5H), 3.69 (s, 3H), 3.57-3.32 (m, 1.5H),3.30-3.16 (m, 1.5H), 3.01 (t, 0.5H), 2.77 (t, 0.5H), 2.62-2.40 (m, 1H),2.32-2.18 (m, 2H), 2.08-1.91 (m, 1H), 1.82-1.32 (m, 8H), 1.22-0.97 (m,2H), 0.97-0.78 (m, 12H)

Synthesis of(1-{(S)-2-[(S)-3-isobutyl-4-(o-nitrophenylsulfonyl)-2-oxo-1-piperazinyl]-4-methylvaleryl}-4-piperidyl)aceticAcid (Part of Method B2)

Sodium hydroxide (1.5 eq.) is added to a solution of methyl(1-{(S)-2-[(S)-3-isobutyl-4-(o-nitrophenylsulfonyl)-2-oxo-1-piperazinyl]-4-methylvaleryl}-4-piperidyl)acetate (1eq.) in a mixture methanol/water. The solution is stirred at roomtemperature overnight then acidified and extracted to yield the titledcompound as a light yellow solid.

¹H NMR (300 MHz, CDCl₃), δ (ppm): 8.14-8.07 (m, 1H), 7.81-7.67 (m, 3H),5.67-5.60 (m, 0.5H), 5.56-5.48 (m, 0.5H), 4.55-4.40 (m, 2H), 4.24-4.14(m, 0.5H), 4.00-3.88 (m, 1.5H), 3.58-3.34 (m, 1.5H), 3.31-3.16 (m,1.5H), 3.07-2.96 (m, 0.5H), 2.81-2.69 (m, 0.5H), 2.62-2.41 (m, 1H),2.36-2.22 (m, 2H), 2.09-1.91 (m, 1H), 1.86-1.32 (m, 8H), 1.25-0.99 (m,2H), 0.97-0.77 (m, 12H)

MS⁻: 579 (M−H)

Synthesis of(S)-1-[(S)-3-methyl-1-({4-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-1-piperidyl}carbonyl)butyl]-3-isobutyl-4-(o-nitrophenylsulfonyl)-2-piperazinone(Part of Method B2)

Oxalyl chloride (2 eq.) is added to a cooled solution of(1-{(S)-2-[(S)-3-isobutyl-4-(o-nitrophenylsulfonyl)-2-oxo-1-piperazinyl]-4-methylvaleryl}-4-piperidyl)aceticacid (1 eq.) and catalytic DMF in DCM. The solution is stirred at roomtemperature for 3 hours then 1-methylpiperazine (5 eq.) is added at 0°C. and the solution is stirred at room temperature overnight.Concentration and flash chromatography purification yield to the titlecompound as a light yellow gum.

¹H NMR (300 MHz, CDCl₃), δ (ppm): 8.10-8.04 (m, 1H), 7.82-7.67 (m, 3H),5.67-5.60 (m, 0.6H), 5.53-5.46 (m, 0.4H), 4.55-4.39 (m, 2H), 4.20-4.11(m, 0.6H), 3.97-3.85 (m, 1.4H), 3.70-3.60 (m, 2H), 3.56-3.32 (m, 3.6H),3.28-3.15 (m, 1.4H), 3.02 (t, 0.6H), 2.74-2.62 (m, 0.4H), 2.62-2.43 (m,1H), 2.43-2.34 (m, 4H), 2.34-1.96 (m, 6H), 1.87-1.33 (m, 8H), 1.25-0.97(m, 2H), 0.96-0.80 (m, 12H)

Synthesis of(S)-1-[(S)-3-methyl-1-({4-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-1-piperidyl}carbonyl)butyl]-3-isobutyl-2-piperazinone(part of Method B2)

A mixture of(S)-1-[(S)-3-methyl-1-({4-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-1-piperidyl}carbonyl)butyl]-3-isobutyl-4-(o-nitrophenylsulfonyl)-2-piperazinone(1 eq.), polymer-supported benzyl mercaptan (2.5-5 eq.) and cesiumcarbonate (3 eq.) in DMF is shaken at room temperature overnight. Afterfiltration, concentration, and flash chromatography purification ifnecessary, the title compound is obtained as a light yellow gum.

¹H NMR (300 MHz, CD₃OD), δ (ppm): 5.62-5.52 (m, 1H), 4.56-4.42 (m, 1H),4.18-4.01 (m, 1H), 3.67-3.56 (m, 4H), 3.47-3.41 (m, 1H), 3.39-3.29 (m,2H), 3.19-3.04 (m, 2H), 3.00-2.87 (m, 1H), 2.79-2.63 (m, 1H), 2.50-2.40(m, 4H), 2.40-2.35 (m, 2H), 2.33 (s, 3H), 2.14-2.00 (m, 1H), 1.90-1.46(m, 8H), 1.27-1.04 (m, 2H), 1.02-0.92 (m, 12H)

MS⁺: 478 (M+H), 500 (M+Na).

Examples 1-319

The following compounds have been synthesized according to the methodsoutlined supra and the compounds have been characterized by their nmrsignals. Synthesesis of precursor I was according to Method C. Startingmaterial for precursor I used was as indicated in Table 1. Synthesesisof precursor II and III was as indicated in Tables 2 and 3 below.

TABLE 1 Starting material for precursor I Ex./Cmpd. # Precursor IaPrecursor Ib Precursor Ic 1-7, 9-32, 36-47, N-(2-nosyl)-L-leucineL-leucine methyl ester 1,2-dibromoethane 52-60, 63-87, hydrochloride95-103, 111, 124, 125, 135-138, 141-229 8, 33, 34, 109(S)-3-cyclopropyl-2-(o- Methyl (S)-2-amino-3- 1,2-dibromoethanenitrophenylsulfonylamino)propionic cyclopropylpropionate acidhydrochloride 35, 115, 133, N-(2-nosyl)-L-α-neopentylglycine Methyl(S)-2-amino-3- 1,2-dibromoethane 134 cyclopropylpropionate hydrochloride48, 51, 88 N-(2-nosyl)-L-leucine L-phenylalanine methyl1,2-dibromoethane ester hydrochloride 49, 50, 90 N-(2-nosyl)-L-leucineL-valine methyl ester 1,2-dibromoethane hydrochloride 61, 62, 91(S)-3-cyclopropyl-2-(o- L-leucine methyl ester 1,2-dibromoethanenitrophenylsulfonylamino)propionic hydrochloride acid  89N-(2-nosyl)-L-phenylalanine L-leucine methyl ester 1,2-dibromoethanehydrochloride  92 (S)-3-cyclopropyl-2-(o- Methyl (S)-2-1,2-dibromoethane nitrophenylsulfonylamino)propionic aminovalerate acidhydrochloride  93 (S)-3-cyclopropyl-2-(o- Methyl (S)-2-1,2-dibromoethane nitrophenylsulfonylamino)propionic aminohexanoate acidhydrochloride  94 (S)-3-cyclopropyl-2-(o- Methyl (S)-2-amino-1,2-dibromoethane nitrophenylsulfonylamino)propionic4,4-dimethylvalerate acid hydrochloride 104 N-(2-nosyl)-L-leucine Methyl(S)-2- 1,2-dibromoethane aminohexanoate hydrochloride 105N-(2-nosyl)-L-leucine Methyl (S)-2-amino-3- 1,2-dibromoethanecyclopropylpropionate hydrochloride 106 N-(2-nosyl)-L-norleucine Methyl(S)-2-amino-3- 1,2-dibromoethane cyclopropylpropionate hydrochloride 107N-(2-nosyl)-L-norleucine Methyl (S)-2- 1,2-dibromoethane aminohexanoatehydrochloride 108 N-(2-nosyl)-L-norleucine Methyl (S)-2-1,2-dibromoethane aminovalerate hydrochloride 110N-(2-nosyl)-L-norleucine L-leucine methyl ester 1,2-dibromoethanehydrochloride 112 N-(2-nosyl)-L-α-neopentylglycine Methyl (S)-2-1,2-dibromoethane aminovalerate hydrochloride 113N-(2-nosyl)-L-α-neopentylglycine Methyl (S)-2- 1,2-dibromoethaneaminohexanoate hydrochloride 114 N-(2-nosyl)-L-α-neopentylglycineL-leucine methyl ester 1,2-dibromoethane hydrochloride 116N-(2-nosyl)-L-leucine Methyl (S)-2-amino- 1,2-dibromoethane4,4-dimethylvalerate hydrochloride 117 N-(2-nosyl)-L-norvaline Methyl(S)-2-amino- 1,2-dibromoethane 4,4-dimethylvalerate hydrochloride 118N-(2-nosyl)-L-α-neopentylglycine Methyl (S)-2-amino- 1,2-dibromoethane4,4-dimethylvalerate hydrochloride 119, 139 N-(2-nosyl)-L-leucineL-alanine methyl ester 1,2-dibromoethane hydrochloride 120N-(2-nosyl)-L-leucine Methyl (S)-2-amino-3- 1,2-dibromoethanecyclohexylpropionate hydrochloride 121, 140 N-(2-nosyl)-L-alanineL-leucine methyl ester 1,2-dibromoethane hydrochloride 122(S)-3-cyclohexyl-2-(o- L-leucine methyl ester 1,2-dibromoethanenitrophenylsulfonylamino) hydrochloride propionic acid 123N-(2-nosyl)-L-norleucine Methyl (S)-2-amino- 1,2-dibromoethane4,4-dimethylvalerate hydrochloride 126 N-(2-nosyl)-L-leucineL-isoleucine methyl 1,2-dibromoethane ester hydrochloride 127N-(2-nosyl)-L-isoleucine L-leucine methyl ester 1,2-dibromoethanehydrochloride 128 N-(2-nosyl)-L-norvaline L-leucine methyl ester1,2-dibromoethane hydrochloride 129 N-(2-nosyl)-L-norvaline Methyl(S)-2- 1,2-dibromoethane aminohexanoate hydrochloride 130N-(2-nosyl)-L-norvaline Methyl (S)-2- 1,2-dibromoethane aminovaleratehydrochloride 131 N-(2-nosyl)-L-leucine Methyl (S)-2- 1,2-dibromoethaneaminovalerate hydrochloride 132 N-(2-nosyl)-L-norvaline Methyl(S)-2-amino-3- 1,2-dibromoethane cyclopropylpropionate hydrochloride

All starting materials for precursor I have been obtained fromSigma-Aldrich, except (S)-2-Amino-3-cyclohexylpropionic acid,(S)-2-Amino-3-cyclopropylpropionic acid, Methyl (S)-2-aminovaleratehydrochloride, Methyl (S)-2-aminohexanoate hydrochloride and Methyl(S)-2-amino-3-cyclohexylpropionate hydrochloride, (all Combi-Blocks),Methyl (S)-2-amino-4,4-dimethylvalerate hydrochloride (Enamine BB), andMethyl (S)-2-amino-3-cyclopropylpropionate hydrochloride (ActivateScientific).

TABLE 2 Compounds made through Method A Characteristic Ex. ¹H NMR CmpdPrecursor II signals Structure # name synthesis (300 MHz) Activity

 1 (S)-1-[(S)-3-Methyl- 1-({4-[(1-methyl- 1H-imidazol-2- yl)methyl]-1-piperidyl}carbonyl) butyl]-4-acetyl-3- isobutyl-2- piperazinone1-methyl-2-[(4- piperidyl)methyl]- 1H-imidazole (Enamine BB) CD₃OD: δ6.98, (s, 1H), 3.64 (br s, 3H), 2.17 (m, 3H), 0.98 (m, 12H) +++

 2 (S)-1-[(S)-3-Methyl- 1-({4-[(1-methyl- 1H-imidazol-2- yl)methyl]-1-piperidyl}carbonyl) butyl]-4- (cyclopropylmethyl)- 3-isobutyl-2-piperazinone 1-methyl-2-[(4- piperidyl)methyl]- 1H-imidazole (EnamineBB) CD₃OD: δ 6.97 (s, 1H), 3.64 (br s, 3H), 0.95 (m, 14H), 0.15 (m, 2H)+++

 3 Ethyl 1-{(S)-2-[(S)- 3-isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- methyl-4- piperidine- carboxylate Ethyl 4-methyl- 4-piperidine- carboxylate (Combi- Blocks) CD₃OD: δ 5.47 (m, 1H), 2.11-1.93 (br m, 2H), 1.22-1.12 (m, 6H), 0.88 (m, 12H) ++

 4 Methyl (1-{(S)-2- [(S)-3-isobutyl-2- oxo-1-piperazinyl]-4-methylvaleryl}-4- piperidyl)acetate Methyl (4- piperidyl)acetate(Combi-Blocks) CD₃OD: δ 5.55 (m, 1H), 4.47 (t, 1H), 3.66 (s, 3H), 2.30(d, 2H), 0.95 (m, 12H) ++

 5 (1-{(S)-2-[(S)-3- Isobutyl-2-oxo-1- piperazinyl]-4- methylvaleryl}-4-piperidyl)acetamide (4-Piperidyl) acetamide (Enamine BB) CD₃OD: δ 5.56(m, 1H), 4.47 (t, 1H), 2.15 (m, 2H), 2.03 (m, 1H), 0.95 (m, 12H) +*

 6 (S)-1-[(S)-3-Methyl- 1-({4-[2- (methylamino)-2- oxoethyl]-1-piperidyl}carbonyl) butyl]-3-isobutyl-2- piperazinone 1- (Methylamino)-2-(4-piperidyl)-1- ethanone (Enamine BB) CD₃OD: δ 5.55 (m, 1H), 4.46 (t,1H), 2.71 (s, 3H), 1.24-1.03 (br m, 3H), 0.95 (m, 12H) +*

 7 (S)-1-[(S)-1-({4-[2- (Dimethylamino) ethyl]-1- piperidyl}carbonyl)-3-methylbutyl]-3- isobutyl-2- piperazinone tert-Butyl 4-(2-hydroxyethyl)-1- piperidine- carboxylate; DMP oxidation to aldehyde,reductive amination with dimethylamine, BOC removal CD₃OD: δ 5.55 (m,1H), 4.46 (t, 1H), 2.43 (t, 2H), 2.29 (s, 6H), 0.95 (m, 12H) ++++

 8 (S)-1-[(S)-2-(4-{2- [N- Ethyl(isopropyl) amino]-2-oxoethyl}-1-piperidyl)-1- (cyclopropylmethyl)- 2-oxoethyl]-3- (cyclopropylmethyl)-2-piperazinone (1-tert- Butoxycarbonyl- 4- piperidyl)acetic acid: amidecoupling with N- Ethyl(isopropyl) amine, BOC removal CD₃OD: δ 5.55 (m,1H), 1.27- 1.08 (br m, 12H), 0.47 (m, 4H), 0.13 (m, 4H) +*

 9 (S)-1-[(S)-3-Methyl- 1-({4-[(1-methyl- 1H-imidazol-2- yl)methyl]-1-piperidyl}carbonyl) butyl]-3-isobutyl-4- (2-methoxyethyl)-2-piperazinone 1-methyl-2-[(4- piperidyl)methyl]- 1H-imidazole (EnamineBB) CD₃OD: δ 6.98 (s, 1H), 6.86 (s, 1H), 5.55 (m, 1H), 3.64, (s, 3H),3.32 (m, 3H), 0.95 (m, 14H) +++

 10 (S)-1-{(S)-3-Methyl- 1-[(4-phenethyl-1- piperidyl)carbonyl]butyl}-3-isobutyl-2- piperazinone 4- phenethyl- piperidine (Enamine BB)CD₃OD: δ 7.29-7.11 (br m, 5H), 5.57 (m, 1H), 1.81 (m, 4H), 1.57 (m, 7H),0.96 (m, 13H) +++

 11 (S)-1-[(S)-3-Methyl- 1-({4-[(3- pyridyl)methyl]-1-piperidyl}carbonyl) butyl]-3-isobutyl-2- piperazinone 3-(piperidin-4-ylmethyl)pyridine (Enamine BB) CD₃OD: δ 8.39 (m, 2H), 7.41 (m, 1H), 7.18(m, 1H), 5.53 (m, 1H), 4.51 (t, 1H), 0.89 (m, 14H) +++

 12 Ethyl (1-{(S)-2-[(S)- 3-isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyl)acetate Ethyl (4- piperidyl)acetate(Combi-Blocks) CD₃OD: δ 5.64 (m, 1H), 4.56 (t, 1H), 4.21 (q, 2H), 2.37(m, 2H), 1.33 (t, 3H), 1.04 (m, 12H) +++

 13 (S)-1-[(S)-1-({4-[2- (Dimethylamino)- 2-oxoethyl]-1-piperidyl}carbonyl)- 3-methylbutyl]-3- isobutyl-2- piperazinone 1-(Dimethylamino)- 2-(4-piperidyl)- 1-ethanone (Enamine BB) CD₃OD: δ 5.61(m, 1H), 4.53 (t, 1H), 3.12 (s, 3H), 2.99 (s, 3H), 2.40 (m, 3H), 1.01(m, 12H) +*

 14 (S)-1-{(S)-1-[(4- Benzyl-1- piperidyl)carbonyl]- 3-methylbutyl}-3-isobutyl-2- piperazinone 4-Benzyl- piperidine CD₃OD: δ 7.18 (m, 5H),5.57 (m, 1H), 4.52 (t, 1H), 1.67 (m, 10H), 0.93 (m, 12H) +++

 15 (S)-1-{(S)-1-[(4- Isopentyl-1- piperidyl)carbonyl]-3-methylbutyl}-3- isobutyl-2- piperazinone 4-Isopentyl- piperidine(Enamine BB) CD₃OD: δ 5.54 (m, 1H), 4.48 (t, 1H), 1.58 (m, 12H), 1.14(m, 4H), 0.93 (m, 12H), 0.81 (m, 6H) +++

 16 (S)-1-[(S)-1-{(8- Azaspiro[4.5]decan- 8-oyl)carbonyl}-3-methylbutyl]-3- isobutyl-2- piperazinone 8-azaspiro[4.5] decan-1-one(Enamine BB) CDCl3: δ, 5.56 (q, 1H), 4.45 (t, 1H), 2.35 (m 2H), 0.95,(m, 12H). ++

 17 (S)-1-[(S)-3-Methyl- 1-({4-[(1-methyl-4- methyl-1H- imidazol-2-yl)methyl]-1- piperidyl}carbonyl) butyl]-3-isobutyl-2- piperazinone2-(4- piperidyl)ethanol; tBOC protection, oxidation to aldehyde, N-methyl imidazole construction (Amide formation, oxidation, cyclization),tBOC removal CD₃OD: δ 6.65 (s, 1H), 5.56 (q, 1H), 4.57 (t, 1H), 3.51 (s,3H), 2.15 (s, 3H), 0.95 (m, 12H). ++

 18 (S)-1-[(S)-1-({4-[(1- Cyclopropyl-1H- imidazol-2- yl)methyl]-1-piperidyl}carbonyl)- 3-methylbutyl]-3- isobutyl-2- piperazinone 2-(4-piperidyl)ethanol; tBOC protection, oxidation to aldehyde, N-cyclopropylamine imidazole construction (with ammonia, cyclopropylamineand glyoxal), tBOC removal CD₃OD: δ, 6.95 (s, 1H), 6.82 (s, 1H), 5.50(q, 1H), 4.45 (t, 1H), 0.95, (m, 16H). ++

 19 (S)-1-[(S)-3-Methyl- 1-({4-[(1-methyl-5- methyl-1H- imidazol-2-yl)methyl]-1- piperidyl}carbonyl) butyl]-3-isobutyl-2- piperazinone2-(4- piperidyl)ethanol; tBOC protection, oxidation to aldehyde, N-methyl imidazole construction (Amide formation, oxidation, cydization,tBOC removal CD₃OD: δ, 6.75 (s, 1H), 5.55 (q, 1H), 4.45 (t, 1H), 3.55(s, 3H), 2.50 (s, 3H), 0.96, (m, 12H). ++

 20 (S)-1-[(S)-3-Methyl- 1-({4-[(1-methyl- 4,5-dimethyl-1H- imidazol-2-yl)methyl]-1- piperidyl}carbonyl) butyl]-3-isobutyl-2- piperazinone2-(4- piperidyl)ethanol; tBOC protection, DMP oxidation to aldehyde,imidazole formation with biacetyl, NH₄OAC and methylamine, BOC removal.¹H NMR (CD₃OD) δ 0.89 (m, 12H), 1.22 (m, 1H), 1.67 (m, 8H), 2.67 (m.3H), 3.01 (m, 4H), 3.42 (m, 2H), 3.54 (s, 3H), 5.55 (m, 1H). +++

 21 (S)-1-[(S)-1-({4-[(1- Ethyl-4,5-dimethyl- 1H-imidazol-2-yl)methyl]-1- piperidyl}carbonyl)- 3-methylbutyl]-3- isobutyl-2-piperazinone 2-(4- piperidyl)ethanol; tBOC protection, DMP oxidation toaldehyde, imidazole formation with biacetyl, NH₄OAc and ethylamine, BOCremoval. ¹H NMR (CD₃OD) δ 0.96 (m, 12H), 1.17 (m, 2H), 1.28 (m, 3H),1.54 (m, 3H), 1.74 (m, 6H), 2.04 (m, 1H), 2.67 (m, 3H), 3.96 (m, 2H) +++

 22 (S)-1-[(S)-1-({4-[(1- Isopropyl-4,5- dimethyl-1H- imidazol-2-yl)methyl]-1- piperidyl}carbonyl)- 3-methylbutyl]-3- isobutyl-2-piperazinone 2-(4- piperidyl)ethanol; tBOC protection, DMP oxidation toaldehyde, imidazole formation with biacetyl, NH₄OAc and isopropylamine,BOC removal. ¹H NMR (CD₃OD) δ 0.96 (m, 12H), 1.22 (m, 2H), 1.56 (m, 9H),2.66 (m, 1H), 2.85 (m, 2H), 5.56 (m, 1H) ++

 23 Methyl 1-{(S)-2- [(S)-3-isobutyl-2- oxo-1-piperazinyl]-4-methylvaleryl}-4- piperidine- carboxylate Methyl 4- piperidine-carboxylate CD₃OD: δ 5.49 (m, 1H), 3.61 (m, 3H), 1.93- 1.81 (br m, 2H),0.88 (m, 12H) +*

 24 Ethyl 1-{(S)-2-[(S)- 3-isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidine- carboxylate Ethyl 4- piperidine-carboxylate CD₃OD: δ 5.52 (m, 1H), 1.96- 1.84 (br m, 2H), 1.21 (t, 3H),0.91 (m, 12H) +*

 25 (S)-1-[(S)-1-{[4-(2- Hydroxy-2- methylpropyl)-1-piperidyl]carbonyl}- 3-methylbutyl]-3- isobutyl-2- piperazinone Methyl(4- piperidyl)acetate; benzyl protection, di- methylation, benzylremoval CD₃OD: δ 5.57 (m, 1H), 4.43 (m, 1H), 1.23 (s, 6H), 0.97 (m, 12H)++

 26 (S)-1-[(S)-3-Methyl- 1-{[4-methyl-4- (phenoxymethyl)- 1-piperidyl]carbonyl} butyl]-3-isobutyl-2- piperazinone tert-Butyl 4-(hydroxymethyl)- 4-methyl-1- piperidine- carboxylate (Combi- Blocks);activation of alcohol, substitution with phenol, tBOC removal CD₃OD: δ7.26 (t, 2H), 5.60 (m, 1H), 1.17 (m, 3H), 0.97 (m, 12H) +++

 27 (S)-1-[(S)-3-Methyl- 1-{[4-(1- phenoxyethyl)-1- piperidyl]carbonyl}butyl]-3-isobutyl-2- piperazinone tert-Butyl 4-(1- hydroxyethyl)-1-piperidine- carboxylate (AstaTech); activation of alcohol, substitutionwith phenol, tBOC removal CD₃OD: δ 7.26 (t, 2H), 5.59 (m, 1H), 1.26 (d,3H), 0.96 (m, 12H) +++

 28 (S)-1-[(S)-1-{[4-(1H- Imidazol-2-yl)-1- piperidyl]carbonyl}-3-methylbutyl]-3- isobutyl-2- piperazinone 2-(4-Piperidyl)- 1H-imidazole(Enamine BB) CD₃OD: δ 6.95 (s, 2H), 5.59 (m, 1H), 4.54 (m, 1H), 2.01 (d,2H), 0.95 (m, 12H) +*

 29 (S)-1-[(S)-3-Methyl- 1-({4-[(1-methyl- 1H-imidazol-2- yl)methyl]-1-piperidyl}carbonyl) butyl]-3-isobutyl-2- piperazinone 1-methyl-2-[(4-piperidyl)methyl]- 1H-imidazole (Enamine BB) CD₃OD: δ 6.98 (s, 1H), 6.86(s, 1H), 5.55 (m, 1H), 4.47 (t, 1H), 4.07 (m, 1H), 3.64 (s, 3H), 3.42(m, 1H), 3.33 (m, 1H), 3.19-2.98 (br m, 2H), 2.91 (m, 1H), 2.77-2.57 (brm, 3H), 2.04 (m, 1H), 1.92- 1.02 (br m, 11H), 0.95 (m, 12H) +++

 30 (S)-1-[(S)-3-Methyl- 1-({4-[(1-methyl- 4,5-dipropyl-lH- imidazol-2-yl)methyl]-1- piperidyl}carbonyl) butyl]-3-isobutyl-2- piperazinonep-toluene- sulfonylmethyl isocyanide; alkylation with 1- iodopropane inthe presence of NaOH and NBu₄I, Van Leusen imidazole formation usingbutyraldehyde and methylamine, deprotonation CD₃OD: δ 5.55 (m, 1H), 4.49(t, 1H), 3.58 (s, 3H), 2.57 (t, 2H), 2.50 (t, 2H), 2.03 (m, 1H), 0.95(m, 18H) +++ with nBuLi followed by addition to tert- butyl 4-formyl-1-piperidine- carboxylate, mesylation of alcohol with methanesulfonylchloride, catalytic hydrogenation using Pd/C and H₂ at 40 psi, BOCremoval

 31 (S)-1-[(S)-3-Methyl- 1-({4-[(1-methyl-5- propyl-1H- imidazol-2-yl)methyl]-1- piperidyl}carbonyl) butyl]-3-isobutyl-2- piperazinone p-toluenesulfonyl methyl isocyanide; Van Leusen imidazole formation usingbutyraldehyde and methylamine, deprotonation with nBuLi followed byaddition to tert- butyl 4-formyl-1- CD₃OD: δ 6.66 (s, 1H), 5.55 (m, 1H),4.47 (t, 1H), 3.52 (s, 3H), 2.54 (t, 2H), 2.02 (m, 1H), 0.97 (m, 15H)+++ piperidine- carboxylate, mesylation of alcohol with methanesulfonylchloride, elimination of mesylate at 110° C., catalytic hydrogenationusing Pd/C and H₂ at 40 psi, BOC removal

 32 (S)-1-[(S)-1-{[4-(1H- Imidazol-4-yl)-1- piperidyl]carbonyl}-3-methylbutyl]-3- isobutyl-2- piperazinone 4-(4-Piperidyl)- 1H-imidazole(Enamine BB) CD₃OD: δ 7.68 (s, 1H), 6.87 (s, 1H), 5.59 (m, 1H), 4.54 (m,1H), 2.03 (d, 2H), 0.95 (m, 12H) ++

 33 (S)-1-{(S)-2-[4-(2- Aminoethyl)-1- piperidyl]-1-(cyclopropylmethyl)- 2-oxoethyl}-3- (cyclopropylmethyl)- 2-piperazinone(2TFA) 4-[2-(tert- Butoxycarbonyl- amino)ethyl] piperidine (Combi-Blocks) CD₃OD: δ 5.54 (m, 1H), 2.99 (m, 2H), 0.76- 0.43 (br m, 5H),0.31-0.33- 0.096 (br m, 4H) ++

 34 (S)-1-[(S)-2-(4-{2- [N- Methyl(isopentyl) amino]-2-oxoethyl}-1-piperidyl)-1- (cyclopropylmethyl)- 2-oxoethyl]-3- (cyclopropylmethyl)-2-piperazinone (1-tert- Butoxycarbonyl- 4- piperidyl)acetic acid: amidecoupling with N- Methyl(isopentyl) amine, BOC removal CD₃OD: δ 5.57 (m,1H), 4.50 (t, 1H), 4.09 (t, 1H), 0.96 (m, 6H), 0.47 (m, 4H), 0.14 (m,4H) +*

 35 (S)-1-{(S)-2-[4-(2- Aminoethyl)-1- piperidyl]-1-(cyclopropylmethyl)- 2-oxoethyl}-3- neopentyl-2- piperazinone (2TFA)4-[2-(tert- Butoxy- carbonylamino) ethyl]piperidine (Combi-Blocks)CD₃OD: δ 5.52 (m, 1H), 4.49 (d, 1H), 1.03 (s, 9H), 0.69 (m, 1H), 0.50(m, 2H), 0.16 (m, 2H) ++

 36 (1-{(S)-2-[(S)-3- Isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- ethyl-4- piperidyl)acetamide 1-Boc-4- piperidone,Meidrum's acid condensation, Grignard reaction, amide formation, tBOCremoval CDCl3: δ, 5.70 (m, 1H), 5.50 (t, 1H), 2.18 (2s, 2H), 0.95, (m,15H). ++

 37 (S)-1-[(S)-1-({4-[(1- Cyclopropyl-4,5- dimethyl-1H- imidazol-2-yl)methyl]-1- piperidyl}carbonyl)- 3-methylbutyl]-3- isobutyl-2-piperazinone 2-(4- piperidyl)ethanol; tBOC protection, DMP oxidation toaldehyde, imidazole formation with biacetyl, NH₄OAc andcyclopropylamine, BOC removal. ¹H NMR (CD₃OD) δ 0.96 (m, 12H), 1.17 (m,6H), 1.65 (m, 8H), 2.71 (m, 3H), 5.56 (m, 1H) +++

 38 (S)-1-[(S)-1-[(4-{[1- (Cyclopropylmethyl)- 4,5-dimethyl-1H-imidazol-2- yl]methyl}-1- piperidyl)carbonyl]- 3-methylbutyl]-3-isobutyl-2- piperazinone 2-(4- piperidyl)ethanol; tBOC protection, DMPoxidation to aldehyde, imidazole formation with biacetyl, NH₄OAc andcyclopropyl- methanamine, BOC removal. ¹H NMR (CD₃OD) δ 0.38 (m, 2H),0.61 (m, 2H), 0.95 (m, 12H), 2.61 (m, 3H), 3.82 (m, 2H), 5.56 (m, 1H)+++

 39 (S)-1-[(S)-1-[(4-{2- [N- Methyl(isopentyl) amino]-2-oxoethyl}-4-methyl-1- piperidyl)carbonyl]- 3-methylbutyl]-3- isobutyl-2-piperazinone (4-Methyl-1-tert- butoxycarbonyl- 4- piperidyl)acetic acid(AstaTech) and N,3- dimethylbutan- 1-amine; amide formation, BOCremoval. 1H NMR (CD₃OD) δ 0.96 (m 18H), 1.15 (m, 3H), 1.62 (m, 14H),3.56 (m, 7H), 5.56 (m, 1H) ++

 40 (S)-1-[(S)-1-[(4-{2- [N- Ethyl(isopropyl) amino]-2-oxoethyl}-4-methyl-1- piperidyl)carbonyl]- 3-methylbutyl]-3- isobutyl-2-piperazinone (4-Methyl-1-tert- butoxycarbonyl- 4- piperidyl)acetic acid(AstaTech) and N- Ethyl(isopropyl) amine; amide formation, BOC removal.¹H NMR (CD₃OD) δ 0.96 (m, 12H), 1.19 (m, 12H), 1.63 (m, 10H), 2.40 (m,2H), 5.58 (m, 1H) +*

 41 (S)-1-[(S)-1-[(4-{2- [N- Methyl(isopentyl) amino]-1-methyl-2-oxoethyl}-1- piperidyl)carbonyl]- 3-methylbutyl]-3- isobutyl-2-piperazinone 2-(1-tert- Butoxycarbonyl- 4-piperidyl)pro- pionic acid(AstaTech)and N,3- dimethylbutan- 1-amine; amide formation, BOC removal.¹H NMR (CD₃OD) δ 0.96 (m, 18H), 1.10 (m, 6H), 2.62 (m, 2H), 4.52 (m,1H), 5.56 (m, 1H) ++

 42 (S)-1-[(S)-1-[(4-{2- [N- Ethyl(isopropyl) amino]-1-methyl-2-oxoethyl}-1- piperidyl)carbonyl]- 3-methylbutyl]-3- isobutyl-2-piperazinone 2-(1-tert- Butoxycarbonyl- 4-piperidyl)pro- pionic acid(AstaTech)and N- Ethyl(isopropyl) amine; amide formation, BOC removal.¹H NMR (CD₃OD) δ 0.96 (m, 14H), 1.17 (m, 16H), 1.68 (m, 10H), 5.56 (m,1H) +*

 43 (S)-1-[(S)-3-Methyl- 1-({4-[(2-methyl- 2H-pyrazol-3- yl)methyl]-1-piperidyl}carbonyl) butyl]-3-isobutyl-2- piperazinone 1-Methyl-5-[(4-piperidyl)methyl]- 1H-pyrazole (Enamine) CD₃OD: δ 7.35 (s, 1H), 6.09 (s,1H), 5.55 (m, 1H), 4.48 (t, 1H), 3.78 (s, 3H), 2.88 (m, 1H), 0.95 (m,12H) +++

 44 (S)-1-[(S)-1-{[4-(2- Hydroxyethyl)-1- piperidyl]carbonyl}-3-methylbutyl]-3- isobutyl-2- piperazinone 2-(4- Piperidyl)ethanolCD₃OD: δ 5.56 (m, 1H), 4.47 (t, 1H), 3.62 (t, 3H), 2.67 (q, 1H), 0.95(m, 12H) ++

 45 (S)-1-[(S)-1-{[4- (Hydroxymethyl)- 1- piperidyl]carbonyl}-3-methylbutyl]-3- isobutyl-2- piperazinone (4-Piperidyl) methanol CD₃OD:δ 5.57 (m, 1H), 4.51 (t, 1H), 2.67 (q, 1H), 1.13 (m, 2H), 0.95 (m, 12H)+*

 46 (S)-1-{(S)-1-[(4- Isobutyl-1- piperidyl)carbonyl]- 3-methylbutyl}-3-isobutyl-2- piperazinone 4- Isobutylpiperidine (Enamine BB) CD₃OD: δ5.56 (m, 1H), 4.46 (t, 1H), 2.66 (q, 1H), 1.87-1.38 (br m, 10H),1.20-1.02 (br m, 3H), 1.02- 0.72 (br m, 19H) +++

 47 (S)-1-{(S)-3-Methyl- 1-[(4-propyl-1- piperidyl)carbonyl]butyl}-3-isobutyl-2- piperazinone 4- Propylpiperidine CD₃OD: δ 5.56 (m,1H), 4.46 (t, 1H), 2.64 (q, 1H), 1.92-1.44 (br m, 9H), 1.44-1.19 (br m,4H), 1.19- 0.81 (br m, 17H) +++

 48 (S)-1-[(S)-2-(4-{2- [N- Ethyl(isopropyl) amino]-2-oxoethyl}- 1-piperidyl)-1-benzyl- 2-oxoethyl]-3- isobutyl-2- piperazinone (1-tert-Butoxycarbonyl- 4- piperidyl)acetic acid: amide coupling with N-Ethyl(isopropyl) amine, BOC removal CD₃OD: δ 7.27 (m, 5H), 5.76 (m, 1H),4.52 (m, 2H), 4.09 (m, 2H), 1.25- 1.07 (br m, 12H), 0.96- 0.80 (m, 8H)++

 49 (S)-1-[(S)-1-[(4-{2- [N- Methyl(isopentyl) amino]-2-oxoethyl}- 1-piperidyl)carbonyl]- 2-methylpropyl]- 3-isobutyl-2- piperazinone(1-tert- Butoxycarbonyl- 4- piperidyl)acetic acid; amide coupling withN- Methyl(isopentyl) amine, BOC removal CD₃OD: δ 5.13 (m, 1H), 4.52 (t,1H), 4.25 (m, 1H), 1.01- 0.84 (br m, 19H) +*

 50 (S)-1-[(S)-1-[(4-{2- [N- Ethyl(isopropyl) amino]-2-oxoethyl}- 1-piperidyl)carbonyl]- 2-methylpropyl]- 3-isobutyl-2- piperazinone(1-tert- Butoxycarbonyl- 4- piperidyl)acetic acid: amide coupling withN- Ethyl(isopropyl) amine, BOC removal CD₃OD: δ 5.13 (m, 1H), 4.55 (m,2H), 4.22 (m, 2H), 1.26- 1.07 (br m, 12H), 1.03- 0.81 (br m, 14H) +*

 51 (2-(1-((S)-2-((S)-3- isobutyl-2- oxopiperazin-1-yl)- 3-phenylpropanoyl) piperidin-4-yl)-N- isopentyl-N- methylacetamide(1-tert- Butoxycarbonyl- 4- piperidyl)acetic acid; amide coupling withN- Methyl(isopentyl) amine, BOC removal CD₃OD: δ 7.25 (m, 5H), 5.77 (m,1H), 4.47 (t, 1H), 4.01 (t, 1H), 1.01-0.81 (m, 14H) ++

 52 (6S)-6-(5-{5-[(S)-4- [(S)-1-({4-[2- (Dimethylamino) ethyl]-1-piperidyl}carbonyl)- 3-methylbutyl]-2- isobutyl-3-oxo-1- piperazinyl}pentylamino}-5- oxopentyl)-7-thia- 2.4- diazabicyclo[3.3.0] octan-3-oneN,N-Dimethyl[2- (4-piperidyl)ethyl] amine (Enamine BB) CD₃OD: δ 5.55 (m,1H), 4.49 (m, 2H), 3.19 (m, 6H), 2.28 (s, 6H), 1.91- 1.27 (br m, 25H),1.0-0.87 (br m, 13H) ++

 53 (S)-1-[(S)-3-Methyl- 1-({4-[2-(1- pyrrolidinyl)ethyl]- 1-piperidyl}carbonyl) butyl]-3-isobutyl-2- piperazinone tert-Butyl 4-(2-hydroxyethyl)-1- piperidine- carboxylate, oxidation to aldehyde,reductive amination with pyrrolidine, BOC deprotection CD₃OD: δ 5.56 (m,1H), 4.48 (t, 1H), 2.69 (m, 6H), 1.71 (m, 16H), 0.96 (m, 12H) ++++

 54 (S)-1-[(S)-1-{[4-(2- {N-Methyl[(p- fluorophenyl) methyl]amino}ethyl)-1- piperidyl]carbonyl}- 3-methylbutyl]-3- isobutyl-2-piperazinone tert-Butyl 4-(2- hydroxyethyl)-1- piperidine- carboxylate,oxidation to aldehyde, reductive amination with N-Methyl[(p-fluorophenyl) methyl]amine, BOC removal CD₃OD: δ 7.35 (m, 2H), 7.07 (m,2H), 5.58 (m, 1H), 4.46 (t, 1H), 3.53 (s, 2H), 2.23 (s, 3H), 0.97 (m,12H) ++++

 55 (S)-1-[(S)-3-Methyl- 1-{(9-methyl-3,9- diaza-3- spiro[5.5]undecyl)carbonyl}butyl]-3- isobutyl-2- piperazinone 3-Methyl-3,9-diazaspiro[5.5] undecane (Enamine BB) CD₃OD: δ 5.56 (m, 1H), 2.50 (m,4H), 2.33 (s, 3H), 1.62 (m, 14H), 0.95 (m, 12H) +++

 56 (S)-1-[(S)-3-Methyl- 1-{[4- (phenoxymethyl)- 1- piperidyl]carbonyl}butyl]-3-isobutyl-2- piperazinone 4- (Phenoxymethyl) piperidine (EnamineBB) CD₃OD: δ 7.28 (t, 2H), 6.93 (m, 3H), 5.62 (m, 1H), 4.57 (t, 1H),3.87 (d, 2H), 0.99 (m, 12H) +++

 57 (S)-1-[(S)-1-({4- [(1H-Imidazol-2- yl)methyl]-1-piperidyl}carbonyl)- 3-methylbutyl]-3- isobutyl-2- piperazinone 2-[(4-Piperidyl)methyl]- 1H-imidazole (Enamine BB) CD₃OD: δ 6.86 (s, 2H), 5.45(m, 1H), 4.37 (t, 1H), 2.57 (d, 2H), 0.85 (m, 12H) +++

 58 (S)-1-[(S)-1-({4- [(4,5-Dimethyl-1H- imidazol-2- yl)methyl]-1-piperidyl}carbonyl)- 3-methylbutyl]-3- isobutyl-2- piperazinonetert-Butyl 4-(2- hydroxyethyl)-1- piperidine- carboxylate, oxidation toaldehyde, imidazole formation using ammonium acetate and 2,3-butanedione, BOC deprotection CD₃OD: δ 5.37 (m, 1H), 4.29 (t, 1H), 2.36(d, 2H), 1.90 (s, 6H), 0.77 (m, 12H) +++

 59 (S)-1-[(S)-1-({4- [(1,3-Benzimidazol- 2-yl)methyl]-1-piperidyl}carbonyl)- 3-methylbutyl]-3- isobutyl-2- piperazinone 2-[(4-Piperidyl)methyl]- 1,3- benzimidazole (Enamine BB) CD₃OD: δ 7.45 (dd,2H), 7.14 (dd, 2H), 5.49 (m, 1H), 4.43 (t, 1H), 2.79 (d, 2H), 0.89 (m,12H) ++

 60 (S)-1-[(S)-3-Methyl- 1-({4-[(1-methyl- 1,3-diaza-4,5,6,7-tetrahydro-1H- inden-2-yl)methyl]- 1- piperidyl}carbonyl)butyl]-3-isobutyl-2- piperazinone tert-Butyl 4-(2- hydroxyethyl)-1-piperidine- carboxylate, oxidation to aldehyde, imidazole formationusing ammonium acetate, methylamine and 1,2- cydohexanedione, BOCdeprotection CD₃OD: δ 5.54 (m, 1H), 4.46 (t, 1H), 3.43 (s, 3H), 2.47 (d,2H), 0.94 (m, 12H) +++

 61 (S)-1-[(S)-1-[(4-{2- [N- Methyl(isopentyl) amino]-2-oxoethyl}- 1-piperidyl)carbonyl]- 3-methylbutyl]-3- (cyclopropylmethyl)-2-piperazinone (1-tert- Butoxycarbonyl- 4- piperidyl)acetic acid andN,3- dimethylbutan- 1-amine; amide formation, BOC removal. ¹H NMR(CD₃OD) δ 0.16 (m, 2H), 0.49 (m, 2H), 0.96 (m, 12H), 1.15 (m, 2H), 1.60(m, 11H), 2.33 (m, 2H), 4.08 (m, 1H), 5.56 (m, 1H) ++

 62 (S)-1-[(S)-1-[(4-{2- [N- Ethyl(isopropyl) amino]-2-oxoethyl}- 1-piperidyl)carbonyl]- 3-methylbutyl]-3- (cyclopropylmethyl)-2-piperazinone (1-tert- Butoxycarbonyl- 4- piperidyl)acetic acid and 2-(isopropylamino) ethan-1-ylium; amide formation, BOC removal. ¹H NMR(CD₃OD) δ 0.15 (m, 2H), 0.47 (m, 2H), 0.96 (m, 6H), 1.18 (m, 10H), 1.66(m, 7H), 2.34 (m, 2H), 5.57 (m, 1H) ++

 63 (S)-1-[(S)-1-({4-[3- (Dimethylamino) propyl]-1- piperidyl}carbonyl)-3-methylbutyl]-3- isobutyl-2- piperazinone N,N-dimethyl-3- (piperidin-4-yl)propan-1- amine (Enamine BB) ¹H NMR (CD₃OD) δ 0.99 (m, 14H), 1.29 (m,2H), 1.67 (m, 11H), 2.42 (S, 6H), 2.52 (m, 2H), 4.47 (m, 1H), 5.57 (m,1H) +++

 64 (S)-1-[(S)-1-[(4-{2- [N- Ethyl(isobutyl) amino]ethyl}-1-piperidyl)carbonyl]- 3-methylbutyl]-3- isobutyl-2- piperazinoneN-ethyl-2- methyl-N-(2- (piperidin-4- yl)ethyl)propan- 1-amine (EnamineBB) ¹H NMR (CD₃OD) δ 1.00 (m, 24H), 1.61 (m, 14H), 2.25 (m, 2H), 2.57(m, 5H), 4.08 (m, 1H), 5.56 (m, 1H) +++

 65 (S)-1-{(S)-3-Methyl- 1-[(1′-methyl-4,4′- bipiperidyl-1-yl)carbonyl]butyl}- 3-isobutyl-2- piperazinone 1-methyl-4,4′-bipiperidine dihydrochloride (Matrix Scientific) ¹H NMR (CD₃OD) δ 0.97(m, 12H), 1.14 (m, 4H), 1.56 (m, 14H), 2.39 (s, 3H), 5.56 (m, 1H) +++

 66 (S)-1-[(S)-3-Methyl- 1-{(2-methyl-2,9- diaza-9- spiro[5.5]undecyl)carbonyl}butyl]-3- isobutyl-2- piperazinone 2-methyl-2,9-diazaspiro[5.5] undecane dihydrochloride (Enamine BB) ¹H NMR (CD₃OD) δ0.97 (m, 12H), 1.56 (m, 12H), 3.12 (m, 1H), 5.56 (m, 1H) +++

 67 (S)-1-[(S)-3-Methyl- 1-{(2-methyl-2,7- diaza-7- spiro[3.5]nonyl)carbonyl}butyl]-3- isobutyl-2- piperazinone 2-methyl-2,7-diazaspiro[3.5] nonane dihydrochloride (AstaTech) ¹H NMR (CD₃OD) δ 0.96(m, 12H), 1.68, (m, 10H), 2.68 (s, 3H), 3.64 (m, 6H), 5.54 (m, 1H) ++

 68 (S)-1-[(S)-1-{[4- (Acetylaminomethyl)- 1- piperidyl]carbonyl}-3-methylbutyl]-3- isobutyl-2- piperazinone 1-{[(4- Piperidyl)methyl]amino}-1- ethanone (Enamine BB) CD₃OD: δ 5.56 (m, 1H), 4.48 (t, 1H),2.66 (q, 1H), 1.94 (s, 3H), 1.26-0.80 (br m, 15H) +*

 69 [(2S,4R)-1-{(S)-2- [(S)-3-Isobutyl-2- oxo-1-piperazinyl]-4-methylvaleryl}-2- methyl-4- piperidyl]acetamide tert-Butyl (S)-2-methyl-4-oxo-1- piperidine- carboxylate (AstaTech); Wittig reaction withmethyl (triphenyl- phosphoranylidene) acetate, catalytic hydrogenationusing Pd/C and H₂, conversion of ester to amide CD₃OD: δ 5.60- 4.43 (brm, 1H), 2.10 (m, 2H), 1.92-1.42 (br m, 8H), 1.42-1.05 (br m, 5H), 0.95(m, 12H) +++ using NH₄OH, BOC removal, diastereomeric resolution bycolumn chromatography

 70 [(2S,4S)-1-{(S)-2- [(S)-3-Isobutyl-2- oxo-1-piperazinyl]-4-methylvaleryl}-2- methyl-4- piperidyl]acetamide tert-Butyl (S)-2-methyl-4-oxo-1- piperidine- carboxylate (AstaTech); Wittig reaction withmethyl (triphenyl- phosphoranylidene) acetate, catalytic hydrogenationusing Pd/C and H₂, conversion of ester to amide CD₃OD: δ 5.49 (t, 1H),2.09- 1.69 (br m, 5H), 1.69-1.42 (br m, 4H), 1.42-1.09 (br m, 6H), 0.95(m, 12H) ++ using NH₄OH, BOC removal, diastereomeric resolution bycolumn chromatography

 71 (S)-1-[(S)-3-Methyl- 1-{(3-oxo-2,8- diaza-8- spiro[4.5]decyl)carbonyl}butyl]-3- isobutyl-2- piperazinone 2,8-Diaza-3- spiro[4.5]decanone (Combi- Blocks) CD₃OD: δ 5.59 (t, 1H), 2.30 (d, 2H), 1.82 (m,2H), 1.74-1.40 (br m, 8H), 0.97 (m, 12H) +*

 72 (R)-5-(1-{(S)-2-[(S)- 3-Isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyl)-5- methyl-2,4- imidazolidinedione5-Methyl-5-(4- piperidyl)-2,4- imidazolidinedione (Enamine BB);diastereomeric resolution by column chromatography CD₃OD: δ 5.56 (m,1H), 4.57 (t, 1H), 2.60 (m, 1H), 1.39 (s, 3H), 0.95 (m, 12H) +*

 73 (S)-5-(1-{(S)-2-[(S)- 3-Isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyl)-5- methyl-2,4- imidazolidinedione5-Methyl-5-(4- piperidyl)-2,4- imidazolidinedione (Enamine BB);diastereomeric resolution by column chromatography CD₃OD: δ 5.67- 5.47(br m, 1H), 4.58 (t, 1H), 2.61 (m, 1H), 1.38 (s, 3H), 0.95 (m, 12H) +*

 74 (1-{(S)-2-[(S)-3- Isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- methyl-4- piperidyl)acetamide (4-Methyl-1-tert-butoxycarbonyl- 4- piperidyl)acetic acid (AstaTech); amide coupling withNH₄OH, BOC removal CD₃OD: δ 5.56 (m, 1H), 2.19 (d, 2H), 1.14 (m, 3H),0.95 (m, 12H) ++

 75 (S)-1-[(S)-3-Methyl- 1-({4-[(4-methyl- 1H-imidazol-2- yl)methyl]-1-piperidyl}carbonyl) butyl]-3-isobutyl-2- piperazinone tert-Butyl 4-(2-hydroxyethyl)-1- piperidine- carboxylate, oxidation to aldehyde,imidazole formation using ammonium acetate and pyruvaldehyde, BOCdeprotection CD₃OD: δ 6.59 (s, 1H), 5.52 (m, 1H), 4.45 (t, 1H), 2.57 (d,2H), 0.93 (m, 12H) +++

 76 (S)-1-[(S)-1-({4- [(1H-Imidazol-2- yl)methyl]-4- methyl-1-piperidyl}carbonyl)- 3-methylbutyl]-3- isobutyl-2- piperazinonetert-Butyl 4-(2- hydroxyethyl)-4- methyl-1- piperidine- carboxylate(Combi- Blocks), oxidation to aldehyde, imidazole formation usingammonium acetate and glyoxal, BOC deprotection CD₃OD: δ 6.89 (s, 2H),5.44 (m, 1H), 4.45 (t, 1H), 1.46 (m, 10H), 0.94 (s, 3H), 0.84 (m, 12H)+++

 77 (S)-1-[(S)-3-Methyl- 1-({4-methyl-4-[(1- methyl-1H- imidazol-2-yl)methyl]-1- piperidyl}carbonyl) butyl]-3-isobutyl-2- piperazinonetert-Butyl 4-(2- hydroxyethyl)-4- methyl-1- piperidine- carboxylate(Combi- Blocks), oxidation to aldehyde, imidazole formation usingammonium acetate, methylamine and glyoxal), BOC deprotection CDCl₃: δ7.01 (s, 1H), 6.90 (s, 1H), 5.56 (m, 1H), 3.66 (s, 3H), 1.09 (s, 3H),0.96 (m, 12H) +++

 78 (S)-1-[(S)-1-({4- [(4,5-Diethyl-1H- imidazol-2- yl)methyl]-1-piperidyl}carbonyl)- 3-methylbutyl]-3- isobutyl-2- piperazinonetert-Butyl 4-(2- hydroxyethyl)-1- piperidine- carboxylate, oxidation toaldehyde, imidazole formation using ammonium acetate, and 3,4-hexanedione, BOC deprotection CD₃OD: δ 5.53 (m, 1H), 2.66 (q, 4H), 1.25(t, 6H), 1.01 (m, 12H) ++

 79 (S)-1-[(S)-1-({4- [(4,5-Diethyl-1- methyl-1H- imidazol-2-yl)methyl]-1- piperidyl}carbonyl)- 3-methylbutyl]-3- isobutyl-2-piperazinone tert-Butyl 4-(2- hydroxyethyl)-1- piperidine- carboxylate,oxidation to aldehyde, imidazole formation using ammonium acetate,methylamine and 3,4- hexanedione, BOC deprotection CD₃OD: δ 5.54 (m,1H), 3.73 (s, 3H), 2.69 (m, 4H), 1.22 (m, 6H), 0.99 (m, 12H) +++

 80 (S)-1-[(S)-1-({4-[(5- Ethyl-1-methyl-1H- imidazol-2- yl)methyl]-1-piperidyl}carbonyl)- 3-methylbutyl]-3- isobutyl-2- piperazinone p-toluenesulfonyl methyl isocyanide; Van Leusen imidazole formation usingpropionaldehyde and methylamine, deprotonation with nBuLi followed byaddition to tert- butyl 4-formyl-1- CD₃OD: δ 6.62 (s, 1H), 5.55 (m, 1H),4.48 (t, 1H), 3.51 (s, 3H), 2.57 (q, 2H), 1.25 (t, 3H), 0.95 (m, 12H)+++ piperidine- carboxylate, mesylation of alcohol, elimination ofmesylate by heat, hydrogenation, BOC deprotection

 81 (S)-1-[(S)-1-({4- [(2,3a-Diaza- 4,5,6,7- tetrahydroinden-3-yl)methyl]-1- piperidyl}carbonyl)- 3-methylbutyl]-3- isobutyl-2-piperazinone 2,3a-Diaza- 4,5,6,7- tetrahydroindene (Enamine BB),deprotonation with nBuLi followed by addition to tert- butyl 4-formyl-1-piperidine- carboxylate, mesylation of alcohol, elimination of CD₃OD: δ6.64 (s, 1H), 5.56 (m, 1H), 4.48 (t, 1H), 3.92 (t, 2H), 2.76 (t, 2H),2.64 (d, 2H), 0.96 (m, 12H) +++ mesylate by heat, hydrogenation, BOCdeprotection

 82 (S)-1-[(S)-3-Methyl- 1-({4-[(2- pyridyl)methyl]-1-piperidyl}carbonyl) butyl]-3-isobutyl-2- piperazinone 2-[(4-Piperidyl)methyl] pyridine (Enamine BB) CD₃OD: δ 8.47 (s, 1H), 7.78 (t,1H), 7.30 (m, 2H), 5.57 (m, 1H), 4.48 (t, 1H), 2.76 (d, 2H), 0.97 (m,12H) ++

 83 (1-{(S)-2-[(S)-3- Isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyl) acetonitrile (4- Piperidyl) acetonitrile(Enamine BB) CD₃OD: δ 5.63 (m, 1H), 4.59 (t, 1H), 2.55 (d, 2H), 1.01 (m,12H) +++

 84 (1-{(S)-2-[(S)-3- Isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyl) methanesulfonamide (4- Piperidyl) methane-sulfonamide (AstaTech) CD₃OD: δ 5.66 (m, 1H), 4.55 (m, 1H), 2.09 (d,2H), 1.04 (m, 12H) +*

 85 (1-{(1S)-2-[(S)-3- Isobutyl-4-methyl- 2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyl)acetamide (4-Piperidyl) acetamide (EnamineBB) CDCl₃: δ 5.53 (m, 1H), 4.17 (d, 1H), 3.10- 2.87 (br m, 2H), 2.33 (m,3H), 1.00-0.76 (br m, 12H) ++

 86 (S)-1-[(S)-3-Methyl- 1-({4-[(1-methyl- 1H-imidazol-2- yl)methyl]-1-piperidyl}carbonyl) butyl]-3-isobutyl-4- methyl-2- piperazinone1-methyl-2-[(4- piperidyl)methyl]- 1H-imidazole (Enamine BB) CD₃OD: δ6.97 (s, 1H), 6.85 (s, 1H), 5.52 (m, 1H), 4.47 (t, 1H), 3.64 (s, 3H),2.36 (m, 3H), 1.03-0.81 (br m, 12H) +++

 87 (S)-1-[(S)-3-Methyl- 1-({4-[(1-methyl- 1H-imidazol-2- yl)methyl]-1-piperidyl}carbonyl) butyl]-4- cyclopropyl-3- isobutyl-2- piperazinone1-methyl-2-[(4- piperidyl)methyl]- 1H-imidazole (Enamine BB) CD₃OD: δ6.96 (s, 1H), 6.84 (s, 1H), 5.58 (m, 1H), 4.47 (m, 1H), 3.63 (s, 3H),0.93 (m, 12H), 0.66- 0.33 (br m, 4H) +++

 88 (1-{(S)-2-[(S)-3- Isobutyl-2-oxo-1- piperazinyl]-3-phenylpropionyl}- 4- piperidyl)acetamide (4-Piperidyl) acetamide(Enamine BB) CD₃OD: δ 7.35- 7.15 (br m, 5H), 5.86-5.67 (br m, 1H), 4.46(t, 1H), 2.63 (t, 1H), 0.93-0.81 (br m, 6H) ++

 89 (1-{(S)-2-[(S)-3- Benzyl-2-oxo-1- piperazinyl]-4- methylvaleryl}-4-piperidyl)acetamide (4-Piperidyl) acetamide (Enamine BB) CD₃OD: δ 7.39-7.16 (br m, 5H), 5.58 (m, 1H), 4.46 (t, 1H), 2.68 (q, 1H), 0.94 (m, 6H)+*

 90 (1-{(S)-2-[(S)-3- Isobutyl-2-oxo-1- piperazinyl]-3-methylbutyryl}-4- piperidyl)acetamide (4-Piperidyl) acetamide (EnamineBB) CD₃OD: δ 5.12 (m, 1H), 4.52 (t, 1H), 2.69 (q, 1H), 2.33 (m, 1H),1.00-0.78 (br m, 12H) ND

 91 (1-{(S)-2-[(S)-3- (Cyclopropylmethyl)- 2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyl)acetamide (4-Piperidyl) acetamide (EnamineBB) CD₃OD: δ 5.57 (m, 1H), 4.47 (t, 1H), 2.69 (q, 1H), 0.96 (m, 6H),0.85 (m, 1H), 0.58-0.41 (br m, 2H), 0.26-0.06 (br m, 2H) +*

 92 (1-{(S)-2-[(S)-3- (Cyclopropylmethyl)- 2-oxo-1-piperazinyl]valeryl}- 4- piperidyl)acetamide (4-Piperidyl) acetamide(Enamine BB) CD₃OD: δ 5.46 (m, 1H), 4.48 (t, 1H), 2.69 (q, 1H),1.43-1.01 (br m, 5H), 0.95 (m, 3H), 0.85 (m, 1H), 0.59-0.39 (br m, 2H),0.26- 0.06 (br m, 2H) +*

 93 (1-{(S)-2-[(S)-3- (Cyclopropylmethyl)- 2-oxo-1- piperazinyl]hexanoyl}-4- piperidyl)acetamide (4-Piperidyl) acetamide (Enamine BB)CD₃OD: δ 5.45 (m, 1H), 4.48 (t, 1H), 2.69 (q, 1H), 1.53-1.00 (br m, 7H),1.00-0.75 (br m, 4H), 0.59- 0.39 (br m, 2H), 0.25-0.04 (br m, 2H) +*

 94 (1-{(S)-2-[(S)-3- (Cyclopropylmethyl)- 2-oxo-1- piperazinyl]-4,4-dimethylvaleryl}-4- piperidyl)acetamide (4-Piperidyl) acetamide (EnamineBB) CD₃OD: δ 5.65 (m, 1H), 4.47 (t, 1H), 2.69 (q, 1H), 0.99-0.75 (br m,10H), 1.00-0.75 (br m, 4H), 0.57- 0.40 (br m, 2H), 0.24-0.06 (br m, 2H)ND

 95 (S)-1-{(S)-3-Methyl- 1-[(4- propionylamino-1- piperidyl)carbonyl]butyl}-3-isobutyl-2- piperazinone 1-(4- Piperidylamino)- 1-propanone(Enamine BB) CD₃OD: δ 5.61 (m, 1H), 2.23 (q, 2H), 1.16 (t, 3H), 1.01 (m,12H) +*

 96 (S)-1-[(S)-3-Methyl- 1-{[4-(5-oxo-3- pyrrolidinyl)-1-piperidyl]carbonyl} butyl]-3-isobutyl-2- piperazinone 4-(4-Piperidyl)-2-pyrrolidinone (Enamine BB) CD₃OD: δ 5.59 (m, 1H), 4.54 (t, 1H), 2.37 (m,2H), 1.70 (m, 9H), 1.04 (m, 12H) ++

 97 (S)-1-[(S)-1-{(2,9- Diazaspiro[5.5] undecan-9- oyl)carbonyl}-3-methylbutyl]-3- isobutyl-2- piperazinone 2,9-Diaza-1- spiro[5.5]un-decanone (Combi-Blocks) CD₃OD: δ 5.67 (m, 1H), 3.18 (m, 2H), 1.82 (m,16H), 1.03 (m, 12H) ++

 98 (S)-1-[(S)-1-{[4-(2- Acetylaminoethyl)- 1- piperidyl]carbonyl}-3-methylbutyl]-3- isobutyl-2- piperazinone 1-[2-(4- Piperidyl)ethyl-amino]-1- ethanone (Matrix Scientific) CD₃OD: δ 5.64 (m, 1H), 4.55 (t,1H), 2.01 (s, 3H), 1.04 (m, 12H) +*

 99 8-{(S)-2-[(S)-3- Isobutyl-2-oxo-1- piperazinyl]-4- methylvaleryl}-1,3,8-triaza-2- spiro[4.5]decanone 1,3,8-Triaza-2- spiro[4.5] decanone(AstaTech) CD₃OD: δ 5.58 (m, 1H), 2.71 (d, 2H), 1.68 (m, 10H), 0.94 (m,12H) +*

100 (S)-1-[(S)-3-Methyl- 1-({4-[(1-methyl- 1H-imidazol-2- yl)methyl]-1-piperidyl}carbonyl) butyl]-4-[(p- fluorophenyl) methyl]-3-isobutyl-2-piperazinone 1-methyl-2-[(4- piperidyl)methyl]- 1H-imidazole (EnamineBB) CD₃OD: δ 7.34 (m, 2H) 7.05 (m, 2H), 5.55 (m, 1H), 4.48 (t, 1H), 3.62(s, 3H), 0.93 (m, 12H) ++++

101 3-(1-{(S)-2-[(S)-3- Isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyl) propionamide 3-(4- Piperidyl) propionamide(Enamine BB) CD₃OD: δ 5.63 (m, 1H), 4.53 (t, 1H), 4.14 (m, 1H), 2.31 (m,2H), 1.75 (m, 11H), 1.01 (m, 12H) ++

102 (1-{(S)-2-[(S)-3- Isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-3- piperidyl)acetamide (3-Piperidyl) acetamide (EnamineBB) CD₃OD: δ 5.61 (m, 1H), 2.20 (m, 2H), 1.70 (m, 11H), 0.99 (m, 12H) +*

103 1-{(S)-2-[(S)-3- Isobutyl-2-oxo-1- piperazinyl]-4- methylvaleryl}-4-piperidine- carboxamide 4-Piperidine- carboxamide CD₃OD: δ 5.64 (m, 1H),2.59 (m, 1H), 2.10 (m, 1H), 1.74 (m, 10H), 1.01 (m, 12H) +*

104 (1-{(S)-2-[(S)-3- Isobutyl-2-oxo-1- piperazinyl] hexanoyl}-4-piperidyl)acetamide (4-Piperidyl) acetamide (Enamine BB) CD₃OD: δ 5.43(m, 1H), 4.47 (t, 1H), 2.69 (q, 1H), 1.01-0.82 (br m, 9H) +*

105 (1-{(S)-2-[(S)-3- Isobutyl-2-oxo-1- piperazinyl]-3- cyclopropyl-propionyl}-4- piperidyl)acetamide (4-Piperidyl) acetamide (Enamine BB)CD₃OD: δ 5.55 (m, 1H), 4.48 (t, 1H), 2.69 (q, 1H), 0.95 (m, 6H), 0.66(m, 1H), 0.53-0.35 (br m, 2H), 0.22-0.04 (br m, 2H) +*

106 (1-{(S)-2-[(S)-3- Butyl-2-oxo-1- piperazinyl]-3- cyclopropyl-propionyl}-4- piperidyl)acetamide (4-Piperidyl) acetamide (Enamine BB)CD₃OD: δ 5.56 (m, 1H), 4.48 (t, 1H), 2.69 (q, 1H), 1.50-1.01 (br m, 6H),0.93 (m, 3H), 0.66 (m, 1H), 0.56-0.36 (br m, 2H), 0.22- 0.02 (br m, 2H)ND

107 (1-{(S)-2-[(S)-3- Butyl-2-oxo-1- piperazinyl) hexanoyl}-4-piperidyl)acetamide (4-Piperidyl) acetamide (Enamine BB) CD₃OD: δ 5.45(m, 1H), 4.47 (t, 1H), 2.69 (q, 1H), 1.53-1.01 (br m, 10H), 0.93 (m, 6H)+*

108 (1-{(S)-2-[(S)-3- Butyl-2-oxo-1- piperazinyl]valeryl}- 4-piperidyl)acetamide (4-Piperidyl) acetamide (Enamine BB) CD₃OD: δ 5.46(m, 1H), 4.47 (t, 1H), 2.69 (q, 1H), 1.61-1.01 (br m, 8H), 0.95 (m, 6H)+*

109 (1-{(S)-2-[(S)-3- (Cyclopropylmethyl)- 2-oxo-1- piperazinyl]-3-cyclopropyl- propionyl}-4- piperidyl)acetamide (4-Piperidyl) acetamide(Enamine BB) CD₃OD: δ 5.56 (m, 1H), 4.49 (t, 1H), 2.69 (q, 1H), 0.85 (m,1H), 0.66 (m, 1H), 0.57-0.34 (br m, 4H), 0.23-0.01 (br m, 4H) +*

110 (1-{(S)-2-[(S)-3- Butyl-2-oxo-1- piperazinyl]-4- methylvaleryl}-4-piperidyl)acetamide (4-Piperidyl) acetamide (Enamine BB) CD₃OD: δ 5.57(m, 1H), 4.47 (t, 1H), 2.68 (q, 1H), 1.25-1.05 (br m, 2H), 0.95 (m, 9H)+*

111 (1-{(S)-2-[(S)-3- Isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyloxy) acetamide (4-Piperidyl- oxy)acetamide(AstaTech) CD₃OD: δ 5.65 (m, 1H), 4.07 (s, 2H), 3.51 (m, 1H), 1.77 (m,10H), 1.03 (m, 12H) +*

112 (1-{(S)-2-[(S)-3- Neopentyl-2-oxo- 1- piperazinyl]valeryl}- 4-piperidyl)acetamide (4-Piperidyl) acetamide (Enamine BB) CD₃OD: δ 5.49(m, 1H), 4.51 (t, 1H), 2.19 (d, 2H), 2.06 (m, 2H), 1.03 (m, 12H) +*

113 (1-{(S)-2-[(S)-3- Neopentyl-2-oxo- 1- piperazinyl] hexanoyl}-4-piperidyl)acetamide (4-Piperidyl) acetamide (Enamine BB) CD₃OD: δ 5.46(m, 1H), 4.51 (t, 1H), 2.19 (d, 2H), 2.06 (m, 2H), 1.78 (m, 4H), 1.02(s, 9H), 0.95 (t, 3H) +*

114 (1-{(S)-2-[(S)-3- Neopentyl-2-oxo- 1-piperazinyl]-4-methylvaleryl}-4- piperidyl)acetamide (4-Piperidyl) acetamide (EnamineBB) CD₃OD: δ 5.60 (m, 1H), 4.51 (t, 1H), 2.19 (d, 2H), 2.06 (m, 2H),1.03 (s, 9H), 0.99 (m, 6H) ND

115 (1-{(S)-2-[(S)-3- Neopentyl-2-oxo- 1-piperazinyl]-3-cydopropylpropionyl}- 4- piperidyl)acetamide (4-Piperidyl) acetamide(Enamine BB) CD₃OD: δ 5.58 (m, 1H), 4.52 (t, 1H), 2.20 (d, 2H), 1.03 (s,9H), 0.69 (m, 1H), 0.49 (m, 2H), 0.16 (m, 2H) ++

116 (1-{(S)-2-[(S)-3- Isobutyl-2-oxo-1- piperazinyl]-4,4-dimethylvaleryl}-4- piperidyl)acetamide (4-Piperidyl) acetamide (EnamineBB) CD₃OD: δ 5.68 (m, 1H), 4.51 (t, 1H), 2.08 (m, 2H), 1.82 (m, 4H),0.97 (m, 15H) +*

117 (1-{(S)-2-((S)-2- Oxo-3-propyl-1- piperazinyl]-4,4-dimethylvaleryl}-4- piperidyl)acetamide (4-Piperidyl) acetamide (EnamineBB) CD₃OD: δ 5.70 (m, 1H), 4.52 (t, 1H), 1.85 (m, 3H), 1.69 (m, 1H),0.98 (m, 12H) +*

118 (1-{(S)-2-[(S)-3- Neopentyl-2-oxo- 1-piperazinyl]-4,4-dimethylvaleryl}-4- piperidyl)acetamide (4-Piperidyl) acetamide (EnamineBB) CD₃OD: δ 5.68 (m, 1H), 4.50 (t, 1H), 2.18 (d, 2H), 2.05 (m, 3H),1.81 (m, 2H), 1.02 (s, 9H), 0.96 (d, 9H) +*

119 (1-{(S)-2-[(S)-3- Isobutyl-2-oxo-1- piperazinyl] propionyl}-4-piperidyl)acetamide (4-Piperidyl) acetamide (Enamine BB) CD₃OD: δ 5.51(m, 1H), 4.52 (t, 1H), 2.20 (d, 2H), 1.34 (d, 3H), 0.99 (t, 6H) +*

120 (1-{(S)-2-[(S)-3- Isobutyl-2-oxo-1- piperazinyl]-3-cydohexylpropionyl}- 4- piperidyl)acetamide (4-Piperidyl) acetamide(Enamine BB) CD₃OD: δ 5.64 (m, 1H), 4.52 (t, 1H), 3.48 (dd, 1H), 2.19(d, 2H), 1.80 (m, 10H), 1.00 (s, 6H) ++

121 (1-{(S)-2-((S)-3- Methyl-2-oxo-1- piperazinyl]-4- methylvaleryl}-4-piperidyl)acetamide (4-Piperidyl) acetamide (Enamine BB) CD₃OD: δ 5.63(m, 1H), 4.53 (t, 1H), 3.56 (q, 1H), 2.21 (d, 2H), 1.42 (d, 3H), 1.02(m, 6H) +*

122 (1-{(S)-2-[(S)-3- (Cyclohexylmethyl)- 2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyl)acetamide (4-Piperidyl) acetamide (EnamineBB) CD₃OD: δ 5.59 (m, 1H), 4.50 (t, 1H), 3.50 (dd, 1H), 2.18 (d, 2H),1.77 (m, 10H), 0.99 (m, 6H) ++

123 (1-{(S)-2-[(S)-3- Butyl-2-oxo-1- piperazinyl]-4,4-dimethylvaleryl}-4- piperidyl)acetamide (4-Piperidyl) acetamide (EnamineBB) CD₃OD: δ 5.65 (m, 1H), 4.47 (t, 1H), 2.69 (q, 1H), 1.22-1.00 (br m,2H), 0.93 (m, 12H) +*

124 3-(1-{(S)-2-[(S)-3- Isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-3- piperidyl) propionamide 3-(3- Piperidyl) propionamide(Enamine BB) CD₃OD: δ 5.56 (m, 1H), 4.43- 4.04 (br m, 1H), 2.34-2.16 (brm, 2H), 0.95 (m, 12H) +*

125 2-(1-{(S)-2-[(S)-3- Isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyl) propionamide 2-(1-tert- Butoxycarbonyl-4-piperidyl) propionic acid (AstaTech); amide coupling with NH₄OH, BOCremoval CD₃OD: δ 5.55 (m, 1H), 4.52 (m, 1H), 2.13 (m, 1H), 1.12 (d, 3H),0.95 (m, 12H) +*

126 (1-{(2S,3S)-2-[(S)-3- Isobutyl-2-oxo-1- piperazinyl]-3-methylvaleryl}-4- piperidyl)acetamide (4-Piperidyl) acetamide (EnamineBB) CD₃OD: δ 5.25 (dd, 1H), 4.56 (t, 1H), 2.19 (d, 2H), 1.84 (m, 4H),0.97 (m, 12H) +*

127 {1-[(S)-2-{(S)-3-[(S)- 1-Methylpropyl]-2- oxo-3,4,5,6-tetrahydro-1H- pyrazin-1-yl}-4- methylvaleryl]-4- piperidyl}acetamide(4-Piperidyl) acetamide (Enamine BB) CD₃OD: δ 5.57 (m, 1H), 4.47 (t,1H), 2.14 (d, 2H), 1.78 (m, 3H), 1.51 (m, 2H), 0.96 (m, 12H) +*

128 (1-{(S)-2-[(S)-2- Oxo-3-propyl-1- piperazinyl]-4- methylvaleryl}-4-piperidyl)acetamide (4-Piperidyl) acetamide (Enamine BB) CD₃OD: δ 5.60(m, 1H), 4.50 (t, 1H), 3.14 (m, 2H), 2.17 (d, 2H), 0.99 (m, 9H) +*

129 (1-{(S)-2-[(S)-2- Oxo-3-propyl-1- piperazinyl] hexanoyl}-4-piperidyl)acetamide (4-Piperidyl) acetamide (Enamine BB) CD₃OD: δ 5.48(m, 1H), 4.50 (t, 1H), 3.44 (dd, 2H), 2.17 (d, 2H), 1.45 (m, 4H), 0.97(m, 9H) +*

130 (1-{(S)-2-[(S)-2- Oxo-3-propyl-1- piperazinyl]valeryl}- 4-piperidyl)acetamide (4-Piperidyl) acetamide (Enamine BB) CD₃OD: δ 5.50(m, 1H), 4.51 (t, 1H), 3.12 (m, 2H), 2.18 (d, 2H), 1.78 (m, 6H), 1.48(m, 2H), 0.99 (t, 6H) +*

131 (1-{(S)-2-[(S)-3- Isobutyl-2-oxo-1- piperazinyl]valeryl}- 4-piperidyl)acetamide (4-Piperidyl) acetamide (Enamine BB) CD₃OD: δ 5.49(m, 1H), 4.51 (t, 1H), 3.13 (m, 2H), 2.18 (d, 2H), 1.79 (m, 6H), 0.98(m, 9H) +*

132 (1-{(S)-2-((S)-2- Oxo-3-propyl-1- piperazinyl]-3- cyclopropyl-propionyl}- 4- piperidyl)acetamide (4-Piperidyl) acetamide (Enamine BB)CD₃OD: δ 5.59 (m, 1H), 4.54 (t, 1H), 2.19 (d, 2H), 0.99 (t, 3H), 0.69(m, 1H), 0.49 (m, 2H), 0.16 (m, 2H) +*

133 (S)-1-[(S)-1- (Cyclopropylmethyl)- 2-(4-isobutyl-1- piperidyl)-2-oxoethyl]-3- neopentyl-2- piperazinone 4- Isobutylpiperidine (EnamineBB) CD₃OD: δ 5.58 (q, 1H), 4.54 (t, 1H), 0.96 (m, 9H), 0.85 (d, 6H),0.63 (m, 1H), 0.42 (m, 2H), 0.08 (m, 2H) +++

134 (S)-1-[(S)-1- (Cyclopropylmethyl)- 2-{4-[(1H- imidazol-2-yl)methyl]-1- piperidyl}-2- oxoethyl]-3- neopentyl-2- piperazinone2-[(4- Piperidyl)methyl]- 1H-imidazole (Enamine BB) CD₃OD: δ 6.91 (s,2H), 5.51 (m, 1H), 4.45 (t, 1H), 0.96 (m, 9H), 0.62 (m, 1H), 0.41 (m,2H), 0.08 (m, 2H) +*

135 1-(1-{(S)-2-[(S)-3- Isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-3- piperidyl)-2- imidazolidinone 1-(3-Piperidyl)-2-imidazolidinone (Enamine BB) CD₃OD: δ 5.59 (m, 1H), 4.53 (t, 1H), 2.99(m, 1H), 1.71 (m, 10H), 0.99 (m, 12H) +*

232 (S)-1-[(S)-1-({2- [(Dimethylamino) methyl]-1,4-dioxa- 8-aza-8-spiro[4.5]decyl} carbonyl)-3- methylbutyl]-3- isobutyl-2- piperazinoneBenzyl 4-oxo-1- piperidine- carboxylate, ketalization with Glycerol,mesylation of alcohol, substitution of mesylate using Dimethylamine, Cbzremoval CD₃OD: δ 5.59, (dd, 1H), 4.37 (m, 1H), 2.39 (s, 6H), 0.97 (m,12H) ++++

233 (S)-1-[(S)-1-({1- [(Dimethylamino) methyl]-6-aza-6- spiro[2.5]octyl}carbonyl)-3- methylbutyl]-3- isobutyl-2- pipprazinone tert-Butyl 1-(hydroxymethyl)- 6-aza-6- spiro[2.5]octane carboxylate (Enamine BB),mesylation of alcohol, substitution of mesylate using Dimethylamine, BOCremoval CD₃OD: δ 5.63-5.55, (m, 1H), 2.30 (s, 6H), 1.00-0.93 (m, 12H),0.28 (m, 1H) +++

234 (S)-1-[(S)-1-({3- [(Dimethylamino) methyl]-1-oxa-5- thia-9-aza-9-spiro[5.5]undecyl} carbonyl)-3- methylbutyl]-3- isobutyl-2- piperazinone(2,2-Dimethyl- 1,3-dioxan-5- yl)methanol (Combi-Blocks), mesylation ofalcohol, substitution with potassium thioacetate, reduction ofthioacetate to thiol, ketalization with Benzyl 4-oxo-1- CD₃OD: δ 5.58(dd, 1H), 2.82- 2.72 (m, 1H), 2.53-2.43 (m, 1H), 0.97 (m, 12H) ++++iperidine- carboxylate, mesylation of alcohol, substitution of mesylateusing Dimethylamine, Cbz removal

235 (S)-1-[(S)-1-[(4-{2- [(3R,4S)-3,4- Dimethyl-1- pyrrolidinyl]ethyl}-1- piperidyl)carbonyl]- 3-methylbutyl]-3- isobutyl-2- piperazinonetert-Butyl 4- (formylmethyl)- 1- piperidine- carboxylate, reductiveamination with (3R,4S)-3,4- Dimethyl- pyrrolidine (ChemBridge BB), BOCremoval CD₃OD: δ 5.55 (m, 1H), 4.50 (m, 1H), 2.75 (2s, 6H), 0.96 (m,12H) ++++

236 (S)-1-[(S)-1-({2- [(Dimethylamino) methyl]-7-aza-7- spiro[3.5]nonyl}carbonyl)-3- methylbutyl]-3- isobutyl-2- piperazinone tert-Butyl 2-oxo-7-aza-7- spiro[3.5]nonane carboxylate (AstaTech), Wittig reaction withMethyltriphenyl phosphonium bromide, hydroboration, oxidation toaldehyde, reductive CD₃OD: δ 5.56 (m, 1H), 2.96 (m, 1H), 2.24 (s, 6H),0.95 (m, 12H) *+ amination with Dimethylamine, BOC removal

237 (S)-1-[(S)-3-Methyl- 1-({3- (morpholinomethyl)- 1,5-dioxa-9-aza- 9-spiro[5.5]undecyl} carbonyl)butyl]-3- isobutyl-2- piperazinone Benzyl4-oxo-1- piperidine- carboxylate, ketalization with (2,2-Dimethyl-1,3-dioxan-5- yl)methanol (Combi-Blocks), tosylation of alcohol,substitution of tosylate using Morpholine, Cbz removal CDCl₃: δ 5.56 (t,1H), 2.34 (br s, 4H), 2.26 (t, 2H), 0.90 (m, 12H) ++++

238 (S)-1-[(S)-1-({4-[2- (1- Azetidinyl)ethyl]-1- piperidyl}carbonyl)-3-methylbutyl)-3- isobutyl-2- piperazinone tert-Butyl 4- (formylmethyl)-1- piperidine- carboxylate, reductive amination with Azetidine, BOCremoval CD₃OD: δ 5.56 (m, 1H), 4.47 (m, 1H), 4.08 (m, 1H), 2.63 (m, 3H),2.16 (m, 2H), 1.66 (m, 10H), 1.32 (m, 2H), 1.03 (m, 15H) ++++

239 (S)-1-[(S)-1-({2- (Dimethylamino)- 7-aza-7- spiro[3.5]nonyl}carbonyl)-3- methylbutyl]-3- isobutyl-2- piperazinone tert-Butyl 2-oxo-7-aza-7- spiro[3.5]nonane carboxylate (AstaTech), reductive aminationwith Dimethylamine, BOC removal CD₃OD: δ 5.56 (m, 1H), 2.91 (m, 1H),2.72 (m, 1H), 2.12 (m, 8H), 1.65 (m, 13H), 0.96 (m, 12H) *+

240 (S)-1-[(S)-1-({2- (Dimethylamino)- 8-aza-8- spiro[4.5]decyl}carbonyl)-3- methylbutyl]-3- isobutyl-2- piperazinone tert-Butyl 2-oxo-8- azaspiro[4.5] decane-8- carboxylate (AstaTech), reductive aminationwith Dimethylamine, BOC removal CD₃OD: δ 5.56 (m, 1H), 3.67 (m, 2H),2.91 (m, 1H), 2.71 (m, 1H), 2.31 (s, 6H), 1.63 (m, 17H), 0.97 (m, 12H)++++

241 (S)-1-[(S)-1-({4-[2- (4-Ethyl-1- piperidyl)ethyl]-1-piperidyl}carbonyl)- 3-methylbutyl]-3- isobutyl-2- piperazinonetert-Butyl 4- (formylmethyl)- 1- piperidine- carboxylate, reductiveamination with 4-Ethylpiperidine (AstaTech), BOC removal CD₃OD: δ 5.55(m, 1H), 4.47 (m, 1H), 4.06 (m, 1H), 2.92 (m, 7H), 1.98 (m, 2H), 1.65(m, 14H), 1.12 (m, 24H) ++++

242 (S)-1-[(S)-1-({4-[2- (4,4-Difluoro-1- piperidyl)ethyl]-1-piperidyl}carbonyl)- 3-methylbutyl]-3- isobutyl-2- piperazinonetert-Butyl 4- (formylmethyl)- 1- piperidine- carboxylate, reductiveamination with 4,4- Difluoropiperidine (AstaTech), BOC removal CD₃OD: δ5.56 (m, 1H), 4.47 (m, 1H), 4.08 (m, 2H), 2.57 (m, 6H), 1.75 (m, 15H),1.05 (m, 15H) ++++

243 (S)-1-[(S)-1-({2-[2- (Dimethylamino) ethyl]-1,4-dioxa-8- aza-8-spiro[4.5]decyl} carbonyl)-3- methylbutyl]-3- isobutyl-2- piperazinone,bis formic acid salt Benzyl 4-oxo-1- piperidine- carboxylate,ketalization with 1,2,4-Butanetriol (Combi-Blocks), tosylation ofalcohol, substitution of tosylate using Dimethylamine, Cbz removal,Formic acid treatment CD₃OD: δ 5.56 (m, 1H), 2.89 (s, 6H), 2.12- 1.35(br m, 12H), 1.07- 0.85 (br m, 12H) ++++

244 (S)-1-[(S)-1-({1- [(Dimethylamino) methyl]-7-aza-7- spiro[3.5]nonyl}carbonyl)-3- methylbutyl]-3- isobutyl-2- piperazinone tert-Butyl 1-oxo-7-aza-7- spiro[3.5]nonane carboxylate (AstaTech), Wittig reaction withMethyltriphenyl phosphonium bromide, hydroboration, oxidation toaldehyde, reductive CD₃OD: δ 5.57 (m, 1H), 3.14 (m, 2H), 3.02- 2.64 (brm, 2H), 2.48 (m, 1H), 0.96 (m, 12H) ++++ amination with Dimethylamine,BOC removal

245 (S)-1-[(S)-1-({(S)-3- [(Dimethylamino) methyl]-8-methyl-1,5-dioxa-9-aza-9- spiro[5.5]undecyl} carbonyl)-3- methylbutyl]-3-isobutyl-2- piperazinone (S)-1-[(S)-1- Phenylethyl]-2- methyl-4-piperidinone (AstaTech), ketalization with (2,2-Dimethyl- 1,3-dioxan-5-yl)methanol (Combi-Blocks), tosylation of alcohol, substitution oftosylate with CD₃OD: δ 5.54 (m, 1H), 3.68 (m, 2H), 3.11 (m, 1H), 2.52-2.16 (br m, 9H), 0.95 (m, 12H) ++++ Dimethylamine, catalytichydrogenation

246 (S)-1-[(S)-1-({(R)-8- Methyl-3-[(1- pyrrolidinyl)methyl]-1,5-dioxa-9-aza- 9- spiro[5.5]undecyl} carbonyl)-3- methylbutyl]-3-isobutyl-4-methyl- 2-piperazinone (R)-1-[(S)-1- Phenylethyl]-2-methyl-4- piperidinone (AstaTech), ketalization with (2,2-Dimethyl-1,3-dioxan-5- yl)methanol (Combi-Blocks), tosylation of alcohol,substitution of tosylate with CDCl₃: δ 5.56 (m, 1H), 3.07- 2.76 (br m,2H), 2.33 (s, 3H), 1.09-0.76 (br m, 12H) ++++ Pyrrolidine, catalytichydrogenation

247 (S)-1-[(S)-3-Methyl- 1-({4-[2-(1- pyrrolidinyl)ethyl]- 1-piperidyl}carbonyl) butyl]-4- cyclopropyl-3- isobutyl-2- piperazinonetert-Butyl 4- (formylmethyl)- 1- piperidine- carboxylate, reductiveamination with Pyrrolidine, BOC removal CD₃OD: δ 5.58 (m, 1H), 4.47 (m,1H), 3.58 (m, 1H), 0.94 (m, 12H), 0.62- 0.38 (br m, 4H) ++++

248 (S)-1-[(S)-1-({(S)-8- Methyl-3-[(1- pyrrolidinyl)methyl]-1,5-dioxa-9-aza- 9- spiro[5.5]undecyl} carbonyl)-3- methylbutyl]-3-isobutyl-2- piperazinone (S)-1-[(S)-1- Phenylethyl]-2- methyl-4-piperidinone (AstaTech), ketalization with (2,2-Dimethyl- 1,3-dioxan-5-yl)methanol (Combi-Blocks), tosylation of alcohol, substitution oftosylate with CD₃OD: δ 5.54 (m, 1H), 4.13- 3.90 (m, 2H), 3.78-3.61 (m,2H), 2.74-2.55 (m, 5H), 0.95 (m, 12H) ++++ Pyrrolidine, catalytichydrogenation

249 (S)-1-[(S)-3-Methyl- 1-({4-[2-(1- pyrrolidinyl)ethyl]- 1-piperidyl}carbonyl) butyl]-4-acetyl-3- isobutyl-2- piperazinonetert-Butyl 4- (formylmethyl)- 1- piperidine- carboxylate, reductiveamination with Pyrrolidine, BOC removal CD₃OD: δ 5.51 (m, 1H), 1.52 (m,4H), 2.28 (s, 3H), 0.88 (m, 12H) ++++

250 (S)-1-[(S)-3-Methyl- 1-({3- (piperidinemethyl)- 1,5-dioxa-9-aza-9-spiro[5.5]undecyl} carbonyl)butyl]-3- isobutyl-2- piperazinone Benzyl4-oxo-1- piperidine- carboxylate, ketalization with (2,2-Dimethyl-1,3-dioxan-5- yl)methanol (Combi-Blocks), tosylation of alcohol,substitution of tosylate using Piperidine, Cbz removal CD₃OD: δ 5.61 (t,1H), 3.16 (m, 1H), 2.23 (t, 2H), 1.59- 1.35 (m, 10H), 0.97 (m, 12H) ++++

251 (S)-1-[(S)-1-({3- [(Dimethylamino) methyl]-1,5-dithia- 9-aza-9-spiro[5.5]undecyl} carbonyl)-3- methylbutyl]-3- isobutyl-2- piperazinone3-Bromo-2- (bromomethyl) propionic acid (AstaTech), substitution withpotassium thioacetate, esterification of carboxylic acid, reduction withLAH, thio- ketalization with Benzyl 4-oxo-1- piperidine- CD₃OD: δ 5.58(t, 1H), 2.62 (m, 2H), 2.21 (s, 6H) 1.72- 1.36 (m, 6H) 0.97 (m, 12H)++++ carboxylate, mesylation of alcohol, substitution of mesylate usingDimethylamine, Cbz removal

252 (1R,5S,6S)-6-(5-{5- [(S)-4-[(S)-1-({(S)-8- Methyl-3-[(1-pyrrolidinyl)methyl]- 1,5-dioxa-9-aza- 9- spiro[5.5]undecyl}carbonyl)-3- methylbutyl]-2- isobutyl-3-oxo-1- piperazinyl]pentyl-amino}-5- (S)-1-[(S)-1- Phenylethyl]-2- methyl-4- piperidinone(AstaTech), ketalization with (2,2-Dimethyl- 1,3-dioxan-5- yl)methanol(Combi-Blocks), tosylation of alcohol, CD₃OD: δ 5.54 (m, 1H), 4.51 (m,1H), 4.32 (m, 1H), 4.12- 3.36 (br m, 4H), 1.89-1.15 (br m, 25H), 0.97(m, 12 H) ++++ oxopentyl)-7-thia- substitution of 2.4- tosylate withdiazabicyclo[3.3.0] Pyrrolidine, octan-3-one catalytic hydrogenation

253 (3S)-1-[(2S)-4- methyl-1-oxo-1- [(3s,6s,8S)-8- methyl-3-[(4-methylpiperidin-1- yl)methyl]-1,5- dioxa-9- azaspiro[5.5] undecan-9-yl]pentan-2- yl]-3-(2- methylpropyl) piperazin-2-one (^(≠)), isomer Z(S)-1-[(S)-1- Phenylethyl]-2- methyl-4- piperidinone (AstaTech),ketalization with (2,2-Dimethyl- 1,3-dioxan-5- yl)methanol(Combi-Blocks), tosylation of alcohol, separation off and Z isomer,substitution of tosylate with 4- Methylpiperidine, catalytichydrogenation CD₃OD: δ 5.54 (m, 1H), 3.92 (m, 2H), 3.69 (m, 2H), 2.27(d, 2H), 0.97 (m, 15H) ++++

254 (3S)-1-[(2S)-4- methyl-1-oxo-1- [(3r,6r,8S)-8- methyl-3-[(4-methylpiperidin-1- yl)methyl]-1,5- dioxa-9- azaspiro[5.5] undecan-9-yl]pentan-2- yl]-3-(2- methylpropyl) piperazin-2-one (^(≠)), isomer E(S)-1-[(S)-1- Phenylethyl]-2- methyl-4- piperidinone (AstaTech),ketalization with (2,2-Dimethyl- 1,3-dioxan-5- yl)methanol(Combi-Blocks), tosylation of alcohol, separation off and Z isomer,substitution of tosylate with 4- Methylpiperidine, catalytichydrogenation CD₃OD: δ 5.54 (m, 1H), 3.99 (m, 2H), 3.69 (m, 2H), 2.35(d, 2H), 0.97 (m, 15H) ++++

255 (S)-1-[(S)-1-({9- (Dimethylamino)- 3-aza-3- spiro[5.5]undecyl}carbonyl)-3- methylbutyl]-3- isobutyl-2- piperazinone tert-Butyl 9-oxo-3-aza-3- spiro[5.5] undecane- carboxylate (AstaTech), reductiveamination with Dimethylamine, BOC removal CD₃OD: δ 5.55 (m, 1H), 2.30(s, 6H), 2.22 (m, 1H), 0.96 (m, 12H) +++

256 (S)-1-[(S)-1-({9- [(Dimethylamino) methyl]-3-aza-3-spiro[5.5]undecyl} carbonyl)-3- methylbutyl]-3- isobutyl-2- piperazinonetert-Butyl 9-oxo- 3-aza-3- spiro[5.5] undecane- carboxylate (AstaTech),Wittig reaction with Methyltriphenyl phosphonium bromide, hydroboration,oxidation to aldehyde, CD₃OD: δ 5.58 (m, 1H), 3.15 (td, 1H), 2.92 (td,1H), 2.25 (s, 6H), 0.98 (m, 12H) ++++ reductive amination withDimethylamine, BOC removal

257 (35)-1-[(2S)-4- methyl-1-oxo-1- [(3r,6r,8S)-8- methyl-3-(pyrrolidin-1- ylmethyl)-1,5- dioxa-9- azaspiro[5.5] undecan-9-yl]pentan-2- yl]-3-(2- methylpropyl) piperazin-2-one (^(≠)), isomer E(S)-1-[(S)-1- Phenylethyl]-2- methyl-4- piperidinone (AstaTech),ketalization with (2,2-Dimethyl- 1,3-dioxan-5- yl)methanol(Combi-Blocks), tosylation of alcohol, separation of E and Z isomer,substitution of tosylate with Pyrrolidine, catalytic hydrogenationCD₃OD: δ 5.53 (m, 1H), 4.45 (m, 1H), 4.10 (m, 2H), 3.75 (m, 2H), 2.33(m, 1H), 1.92 (m, 4H), 0.96 (m, 12H) ++++

258 (3S)-1-[(2S)-4- methyl-1-oxo-1- [(3s,6s,8S)-8- methyl-3-(pyrrolidin-1- ylmethyl)-1,5- dioxa-9- azaspiro[5.5] undecan-9-yl]pentan-2- yl]-3-(2- methylpropyl) piperazin-2-one (^(≠)), isomer Z(S)-1-[(S)-1- Phenylethyl]-2- methyl-4- piperidinone (AstaTech),ketalization with (2,2-Dimethyl- 1,3-dioxan-5- yl)methanol(Combi-Blocks), tosylation of alcohol, separation off and Z isomer,substitution of tosylate with Pyrrolidine, catalytic hydrogenationCD₃OD: δ 5.57 (m, 1H), 4.49 (m, 1H), 4.02 (m, 2H), 3.76 (m, 2H), 2.70(m, 4H), 2.45 (m, 1H), 1.89 (m, 4H), 1.00 (m, 12H) ++++

259 (S)-1-[(S)-1- {[(4aS,8aR)-6- (Dimethylamino) perhydroisoquinol-2-yl]carbonyl}-3- methylbutyl]-3- isobutyl-2- piperazinone tert-Butyl 6-hydroxy- decahydro- isoquinoline-2- carboxylate (Enamine BB), oxidationto ketone, reductive amination with Dimethylamine, BOC removal CDCl₃: δ5.40 (m, 1H), 2.78 (m, 2H), 2.28 and 2.11 (s, 6H), 0.75 (m, 12H) *+

260 (S)-1-[(S)-1-({(S)-8- Methyl-3-(1- methyl-1H- imidazol-2-yl)-1,5-dioxa-9-aza-9- spiro[5.5]undecyl} carbonyl)-3- methylbutyl]-3-isobutyl-2- piperazinone (S)-1-[(S)-1- Phenylethyl]-2- methyl-4-piperidinone (AstaTech), ketalization with (2,2-Dimethyl- 1,3-dioxan-5-yl)methanol (Combi-Blocks), oxidation of alcohol to aldehyde, imidazoleformation (with Glyoxal, methylamine CD₃OD: δ 7.02 (d, 1H), 6.91 (d,1H), 5.55 (m, 1H), 3.71 (s, 3H), 1.08- 0.86 (br m, 12H) ND and ammoniumacetate), catalytic hydrogenation

261 (S)-1-[(S)-1-({4- (Dimethylamino)- 1-oxa-9-aza-9- spiro[5.5]undecyl}carbonyl)-3- methylbutyl]-3- isobutyl-2- piperazinone tert-Butyl 4-oxo-1-oxa-9-aza-9- spiro[5.5] undecane- carboxylate (Enamine BB), reductiveamination with Dimethylamine, BOC removal CD₃OD: δ 5.60-5.52 (m, 1H),4.29-4.10 (m, 1H), 2.68 (s, 6H), 0.97 (m, 12H) +++

262 (S)-1-[(S)-1-({3- (Dimethylamino)- 1,5-dioxa-9-aza-9-spiro[5.5]undecyl} carbonyl)-3- methylbutyl]-3- isobutyl-2- piperazinone2-Amino-1,3- propanediol, Fmoc protection of amine, ketalization withBenzyl 4-oxo-1- piperidine- carboxylate, Fmoc removal, reductiveamination with formaldehyde, Cbz removal CD₃OD: δ 5.58 (dd, 1H), 2.48(m, 1H), 2.34 (s, 6H), 0.96 (m, 12H) ++++

263 (S)-1-[(S)-1-({2- [(Dimethylamino) methyl]-7-aza-7- spiro[3.5]nonyl}carbonyl)-3- methylbutyl]-3- isobutyl-4-methyl- 2-piperazinonetert-Butyl 2-oxo- 7-aza-7- spiro[3.5]nonane carboxylate (AstaTech),Wittig reaction with Methyltriphenyl phosphonium bromide, hydroboration,oxidation to aldehyde, reductive CDCl₃: δ 5.52 (m, 1H), 2.32 (s, 3H),2.19 (s, 6H), 0.93 (m, 15H) ++++ amination with Dimethylamine, BOCremoval

264 (S)-1-[(S)-3-Methyl- 1-{(2-methyl-2,8- diaza-8- spiro[4.5]decyl)carbonyl}butyl]-3- isobutyl-2- piperazinone 2-Methyl-2,8-diazaspiro[4.5] decane (citrate salt, Combi- Blocks) CD₃OD: δ 5.56 (m,1H), 3.13 (m, 1H), 2.91 (m, 1H), 2.78 (m, 2H), 2.45 (s, 3H), 1.66 (m,13H), 0.96 (m, 12H) +++

265 (S)-1-[(S)-1-[(4-{2- [(R)-2-Methyl-1- pyrrolidinyl]ethyl}- 1-piperidyl)carbonyl]- 3-methylbutyl]-3- isobutyl-2- piperazinonetert-Butyl 4- (formylmethyl)- 1- piperidine- carboxylate, reductiveamination with (R)-2- Methylpyrrolidine, BOC removal CD₃OD: δ 5.56 (m,1H), 4.08 (m, 1H), 2.66 (m, 1H), 2.47 (m, 1H), 2.22 (m, 2H), 2.02 (m,1H), 1.67 (m, 14H), 1.13 (m, 5H), 0.96 (m, 12H) ++++

266 (S)-1-[(S)-1-({1- (Dimethylamino)- 7-aza-7- spiro[3.5]nonyl}carbonyl)-3- methylbutyl]-3- isobutyl-2- piperazinone tert-Butyl 1-oxo-7-aza-7- spiro[3.5]nonane carboxylate (AstaTech), reductive aminationwith Dimethylamine, BOC removal CD₃OD: δ 5.56 (m, 1H), 3.13 (m, 1H),2.91 (m, 1H), 2.78 (m, 2H), 2.45 (s, 3H), 1.66 (m, 13H), 0.96 (m, 12H)*+

267 (S)-1-[(S)-1-[(4-{2- [(S)-3-Methyl-1- piperidyl]ethyl}-1-piperidyljcarbonyl]- 3-methylbutyl]-3- isobutyl-2- piperazinonetert-Butyl 4- (formylmethyl)- 1- piperidine- carboxylate, reductiveamination with (S)-3- Methylpiperidine (AstaTech), BOC removal CD₃OD: δ5.56 (m, 1H), 4.47 (m, 1H), 4.08 (m, 1H), 2.67 (m, 1H), 2.39 (m, 2H),1.68 (m, 18H), 1.02 (m, 19H) ++++

268 (S)-1-[(S)-3-Methyl- 1-({4-[2-(4-methyl- 1-piperidyl)ethyl]- 1-piperidyl}carbonyl) butyl]-3-isobutyl-4- methyl-2- piperazinonetert-Butyl 4- (formylmethyl)- 1- piperidine- carboxylate, reductiveamination with 4- Methylpiperidine, BOC removal CD₃OD: δ 5.53 (m, 1H),4.46 (m, 1H), 4.08 (m, 1H), 2.62 (m, 2H), 2.39 (s, 5H), 1.61 (m, 23H),0.93 (m, 15H) ++++

269 (S)-1-[(S)-1-({4-[2- (4,4-Difluoro-1- piperidyl)ethyl]-1-piperidyl}carbonyl)- 3-methylbutyl]-3- isobutyl-4-methyl- 2-piperazinonetert-Butyl 4- (formylmethyl)- 1- piperidine- carboxylate, reductiveamination with 4,4- Difluoropiperidine (AstaTech), BOC removal CD₃OD: δ5.53 (m, 1H), 4.47 (m, 1H), 4.09 (m, 1H), 3.05 (m, 2H), 2.37 (s, 3H),1.75 (m, 15H), 1.00 (m, 15H) *+

270 (S)-1-[(S)-3-Methyl- 1-({4-methyl-4-[2- (1- pyrrolidinyl)ethyl]- 1-piperidyl}carbonyl) butyl]-3-isobutyl-2- piperazinone tert-Butyl 4-(2-hydroxyethyl)-4- methyl-1- piperidine- carboxylate (Combi- Blocks),oxidation to aldehyde, reductive amination with Pyrrolidine, BOC removalCD₃OD: δ 5.55 (m, 1H), 3.19- 3.06 (br m, 1H), 2.00-1.26 (br m, 16H),1.04 (d, 3H), 0.95 (m, 12H) +++

271 (S)-1-[(S)-1-({3- (Dimethylamino)- 1-oxa-8-aza-8- spiro[4.5]decyl}carbonyl)-3- methylbutyl]-3- isobutyl-2- piperazinone tert-Butyl 3-oxo-1-oxa-8- azaspiro[4.5] decane-8- carboxylate (AstaTech), reductiveamination with Dimethylamine, BOC removal CD₃OD: δ 5.55 (m, 1H), 2.24(s, 6H), 2.18- 1.98 (br m, 1H), 1.92-1.40 (br m, 11H), 0.95 (m, 12H)++++

272 (S)-1-[(S)-1-({(S)-8- Methyl-3-[(4- methyl-1- piperidyl)methyl]-1,5-dioxa-9-aza-9- spiro[5.5]undecyl} carbonyl)-3- methylbutyl]-3-isobutyl-2- piperazinone (S)-1-[(S)-1- Phenylethyl]-2- methyl-4-piperidinone (AstaTech), ketalization with (2,2-Dimethyl- 1,3-dioxan-5-yl)methanol (Combi-Blocks), tosylation of alcohol, substitution oftosylate with 4- CD₃OD: δ 5.54 (m, 1H), 3.68 (m, 2H), 3.11 (m, 1H),2.55- 1.90 (br m, 7H), 0.95 (m, 15H) ++++ Methylpiperidine, catalytichydrogenation

273 (S)-1-[(S)-1-({(S)-8- Methyl-3-[(1- pyrrolidinyl)methyl]-1,5-dioxa-9-aza- 9- spiro[5.5]undecyl} carbonyl)-3- methylbutyl]-3-isobutyl-4-methyl- 2-piperazinone (S)-1-[(S)-1- Phenylethyl]-2-methyl-4- piperidinone (AstaTech), ketalization with (2,2-Dimethyl-1,3-dioxan-5- yl)methanol (Combi-Blocks), tosylation of alcohol,substitution of tosylate with CDCl₃: δ 5.50 (t, 1H), 3.00- 2.35 (br m,10H), 2.31 (s, 3H), 1.00-0.80 (br m, 12H) ++++ Pyrrolidine, catalytichydrogenation

274 (3S)-1-[(2S)-4- methyl-1-oxo-1- [(3s,6s,8S)-8- methyl-3-[(²H₈)pyrrolidin-1- ylmethyl]-1,5- dioxa-9- azaspiro[5.5] undecan-9-yl]pentan-2- yl]-3-(2- methylpropyl) piperazin-2-one (^(≠)), isomer Z(S)-1-[(S)-1- Phenylethyl]-2- methyl-4- piperidinone (AstaTech),ketalization with (2,2-Dimethyl- 1,3-dioxan-5- yl)methanol(Combi-Blocks), tosylation of alcohol, separation of E, and Z isomer,substitution of tosylate with CD₃OD: δ 5.54 (m, 1H), 2.46 (m, 3H), 2.07(m, 2H), 0.96 (m, 12H) ++++ Pyrrolidine-d₈, catalytic hydrogenation

275 (S)-1-[(S)-3-Methyl- 1-({4-[2-(1- pyrrolidinyl)ethyl]- 1-piperidyl}carbonyl) butyl]-4-[(p- fluorophenyl) methyl]-3-isobutyl-2-piperazinone tert-Butyl 4- (formylmethyl)- 1- piperidine- carboxylate,reductive amination with Pyrrolidine, BOC removal CD₃OD: δ 7.24 (m, 2H),6.97 (m, 2H), 5.56 (m, 1H), 4.14 (t, 1H), 0.89 (m, 12H) ++++

276 Methyl (S)-4-[(S)-3- methyl-1-({4-[2-(1- pyrrolidinyl)ethyl]- 1-piperidyl}carbonyl) butyl]-2-isobutyl-3- oxo-1- piperazine- carboxylatetert-Butyl 4- (formylmethyl)- 1- piperidine- carboxylate, reductiveamination with Pyrrolidine, BOC removal CD₃OD: δ 5.55 (m, 1H), 3.74 (d,3H), 3.05 (m, 1H), 1.46 (m, 4H), 0.97 (m, 12H) ++++

277 (S)-1-[(S)-3-Methyl- 1-({4-[2-(1- pyrrolidinyl)ethyl]- 1-piperidyl)carbonyl) butyl]-4- (dimethylamino) carbonyl-3-isobutyl-2-piperazinone tert-Butyl 4- (formylmethyl)- 1- piperidine- carboxylate,reductive amination with Pyrrolidine, BOC removal CD₃OD: δ 5.55 (m, 1H),4.48 (d, 2H), 4.00 (m, 1H), 2.81 (d, 6H), 0.97 (m, 12H) *+

278 (S)-1-[(S)-3-Methyl- 1-({3-[(4-methyl-1- piperidyl)methyl]-1,5-dioxa-9-aza-9- spiro[5.5]undecyl} carbonyl)butyl]-3- isobutyl-2-piperazinone Benzyl 4-oxo-1- piperidine- carboxylate, ketalization with(2,2-Dimethyl- 1,3-dioxan-5- yl)methanol (Combi-Blocks), tosylation ofalcohol, substitution of tosylate using 4- Methylpiperidine, Cbz removalCD₃OD: δ 5.59 (t, 1H), 3.91 (br m, 1H), 2.23 (t, 2H), 1.69-1.41 (m, 8H),1.39-1.25 (m, 1H) 0.97 (m, 15H) ++++

279 (3S)-1-[(2S)-4- methyl-1-oxo-1- [(3s,6s,8S)-3-{6-azaspiro[2.5]octan- 6-ylmethyl}-8- methyl-1,5-dioxa- 9- azaspiro[5.5]undecan-9-yl] pentan-2- yl]-3-(2- methylpropyl) piperazin-2-one (^(≠)),isomer Z (S)-1-[(S)-1- Phenylethyl]-2- methyl-4- piperidinone(AstaTech), ketalization with (2,2-Dimethyl- 1,3-dioxan-5- yl)methanol(Combi-Blocks), tosylation of alcohol, separation of E and Z isomer,substitution of tosylate with 6- Azaspiro[2.5] octane (AstaTech),catalytic hydrogenation CDCl₃: δ 5.45 (t, 1H), 4.63 (m, 1H), 1.89 (m,1H), 0.83 (m, 12H), 0.16 (s, 4H) ++++

280 (3S)-1-[(2S)-4- methyl-1-oxo-1- [(3r,6r,8S)-3-{6-azaspiro[2.5]octan- 6-ylmethyl}-8- methyl-1,5-dioxa- 9-azaspiro[5.5]undec an-9-yl]pentan-2- yl]-3-(2- methylpropyl)piperazin-2-one (^(≠)), isomer E (S)-1-[(S)-1- Phenylethyl]-2- methyl-4-piperidinone (AstaTech), ketalization with (2,2-Dimethyl- 1,3-dioxan-5-yl)methanol (Combi-Blocks), tosylation of alcohol, separation of E and Zisomer, CD₃OD: δ 5.54 (m, 1H), 4.01 (m, 2H), 3.71 (m, 2H), 0.97 (m, 12H), 0.30 (s, 4 H) ++++ substitution of tosylate with 6- Azaspiro[2.5]octane (AstaTech), catalytic hydrogenation

281 (S)-1-[(S)-1-[(4-{2- [(R)-3-Methyl-1- piperidyl]ethyl}-1-piperidyl)carbonyl]- 3-methylbutyl]-3- isobutyl-2- piperazinonetert-Butyl 4- (formylmethyl)- 1- piperidine- carboxylate, reductiveamination with (R)-3- Methylpiperidine (AstaTech), BOC removal CD₃OD: δ5.59 (m, 1H), 4.51 (t, 1H), 2.04 (m, 1H), 0.99 (m, 12H), 0.94 (d, 3H)++++

282 (S)-1-[(S)-1-[(4-{2- (6-Aza-6- spiro[2.5]octyl) ethyl}-1-piperidyl)carbonyl]- 3-methylbutyl]-3- isobutyl-2- piperazinonetert-Butyl 4- (formylmethyl)- 1- piperidine- carboxylate, reductiveamination with 6- Azaspiro[2.5] octane (AstaTech), BOC removal CD₃OD: δ5.58 (m, 1H), 4.48 (t, 1H), 3.35 (m, 2H), 3.11 (m, 2H), 0.97 (m, 12H),0.36 (s, 4H) ++++

283 (3S)-1-[(2S)-4- methyl-1-oxo-1- [(3r,6r,8S)-3- (azetidin-1-ylmethyl)-8- methyl-1,5-dioxa- 9- azaspiro[5.5] undecan-9- yl]pentan-2-yl]-3-(2- methylpropyl) piperazin-2-one (^(≠)), isomer E (S)-1-[(S)-1-Phenylethyl]-2- methyl-4- piperidinone (AstaTech), ketalization with(2,2-Dimethyl- 1,3-dioxan-5- yl)methanol (Combi-Blocks), tosylation ofalcohol, separation of E and Z isomer, substitution of tosylate withAzetidine, catalytic hydrogenation CD₃OD: δ 5.54 (m, 1H), 3.96 (m, 2H),3.67 (m, 2H), 2.51 (d, 2H), 1.89- 1.42 (m, 5H), 0.97 (m, 12H) ++++

284 (3S)-1-[(2S)-4- methyl-1-oxo-1- [(3s,6s,8S)-3- (azetidin-1-ylmethyl)-8- methyl-1,5-dioxa- 9- azaspiro[5.5] undecan-9- yl]pentan-2-yl]-3-(2- methylpropyl) piperazin-2-one (^(≠)), isomer Z (S)-1-[(S)-1-Phenylethyl]-2- methyl-4- piperidinone (AstaTech), ketalization with(2,2-Dimethyl- 1,3-dioxan-5- yl)methanol (Combi-Blocks), tosylation ofalcohol, separation of E and Z isomer, substitution of tosylate withAzetidine, catalytic hydrogenation CD₃OD: δ 5.54 (m, 1H), 3.91 (m, 2H),3.69 (m, 2H), 2.52 (d, 2H), 1.7- 1.44 (m, 5H), 0.97 (m, 12H) ++++

285 (S)-1-[(S)-1-({(S)-8- Methyl-3-(2- pyridyl)-1,5-dioxa- 9-aza-9-spiro[5.5]undecyl} carbonyl)-3- methylbutyl]-3- isobutyl-2- piperazinone2-(2-Pyridyl)-1,3- propanediol (Combi-Blocks), ketalization with(S)-1-[(S)-1- Phenylethyl]-2- methyl-4- piperidinone (AstaTech),catalytic hydrogenation CD₃OD: δ 8.51 (s, 1H), 7.80 (t, 1H), 7.51 (dd,1H), 7.31 (t, 1H), 5.56 (m, 1H), 0.97 (m, 12H) ND

286 (S)-1-[(S)-1-({(2′S)- 5- (Dimethylamino)- 2′-methyl- 3a,4,5,6,7,7a-hexahydrospiro [indene-2,4′- piperidin]-1′- yl}carbonyl)-3-methylbutyl]-3- isobutyl-2- piperazinone 4-Amino-1,2- cyclohexanediol(Enamine BB), reductive amination with formaldehyde, ketalization with(S)-1-[(S)-1- Phenylethyl]-2- methyl-4- piperidinone (AstaTech),catalytic hydrogenation CD₃OD: δ 5.55 (m, 1H), 3.12 (m, 1H), 2.91 (m,1H), 2.28 (br, 3, 6H), 1.94-1.44 (m, 13H), 0.96 (m, 12H) ++++

287 (3S)-4-methyl-1- [(2S)-4-methyl-1- oxo-1-[(3s,6s,8S)-8- methyl-3-(pyrrolidin-1- ylmethyl)-1,5- dioxa-9- azaspiro[5.5] undecan-9-yl]pentan-2- yl]-3-(2- methylpropyl) piperazin-2-one (^(≠)), isomer Z(S)-1-[(S)-1- Phenylethyl]-2- methyl-4- piperidinone (AstaTech),ketalization with (2,2-Dimethyl- 1,3-dioxan-5- yl)methanol(Combi-Blocks), tosylation of alcohol, separation of E and Z isomer,substitution of tosylate with Pyrrolidine, catalytic hydrogenationCDCl₃: δ 5.43 (t, 1H), 4.66 (m, 1H), 3.57 (m, 2H), 2.23 (s, 3H), 2.03(m, 1H), 0.83 (m, 12H) ++++

288 (3S)-4-methyl-1- [(2S)-4-methyl-1- oxo-1-[(3r,6r,8S)-8- methyl-3-(pyrrolidin-1- ylmethyl)-1,5- dioxa-9- azaspiro[5.5] undecan-9-yl]pentan-2- yl]-3-(2- methylpropyl) piperazin-2-one (^(≠)), isomer E(S)-1-[(S)-1- Phenylethyl]-2- methyl-4- piperidinone (AstaTech),ketalization with (2,2-Dimethyl- 1,3-dioxan-5- yl)methanol(Combi-Blocks), tosylation of alcohol, separation off and 2 isomer,substitution of tosylate with Pyrrolidine, catalytic hydrogenationCDCl₃: δ 5.45 (t, 1H), 4.67 (m, 1H), 5.92 (m, 2H), 3.63 (m, 2H), 2.26(s, 3H), 1.92 (m, 1H), 0.86 (m, 12H) ++++

289 (S)-1-[(S)-1-[(4-{2- (6-Aza-6- spiro[2.5]octyl) ethyl}-1-piperidyl)carbonyl]- 3-methylbutyl]-3- isobutyl-4-methyl- 2-piperazinonetert-Butyl 4- (formylmethyl)- 1- piperidine- carboxylate, reductiveamination with 6- Azaspiro[2.5] octane (AstaTech), BOC removal CD₃OD: δ5.55 (m, 1H), 4.48 (t, 1H), 2.38 (s, 3H), 0.33 (s, 4H) ++++

290 (3S)-3-(2- methylpropyl)-1- [(2S)-1-oxo-1- [(3s,6s,8S)-8- methyl-3-(pyrrolidin-1- ylmethyl)-1,5- dioxa-9- azaspiro[5.5] undecan-9-yl]propan-2- yl]piperazin-2-one (^(≠)), isomer Z (S)-1-[(S)-1-Phenylethyl]-2- methyl-4- piperidinone (AstaTech), ketalization with(2,2-Dimethyl- 1,3-dioxan-5- yljmethanol (Combi-Blocks), tosylation ofalcohol, separation off and Z isomer, substitution of tosylate withPyrrolidine, catalytic hydrogenation CDCl₃: δ 5.45 (t, 1H), 4.63 (m,1H), 1.89 (m, 1H), 0.83 (m, 12H), 0.16 (s, 4H) ++++

291 (S)-1-[(S)-1-({8,8- Dimethyl-3-[(1- pyrrolidinyl)methyl]-1,5-dioxa-9-aza- 9- spiro[5.5]undecyl} carbonyl)-3- methylbutyl]-3-isobutyl-2- piperazinone 1-Benzyl-2,2- dimethyl-4- piperidinone(AstaTech), ketalization with (2,2-Dimethyl- 1,3-dioxan-5- yl)methanol(Combi-Blocks), tosylation of alcohol, substitution of tosylate withPyrrolidine, catalytic hydrogenation CDCl₃: δ 5.41 (m, 1H), 3.85 (m,2H), 3.55 (m, 2H), 1.38 (s, 6H 0.84 (m, 12H) *+

292 (S)-1-[(S)-1- ({(1R,5S,2′S)-7- (Dimethylamino)- 2′-methylspiro[2.4-dioxabicydo[3.3.0] octane-3,4′- piperidin]-1′- yl}carbonyl)-3-methylbutyl]-3- isobutyl-2- piperazinone (1R,2S,4R)-4- Amino-1,2-cydopentanediol (HCl salt, Enamine BB), reductive amination withFormaldehyde, ketalization with (S)-1-[(S)-1- Phenylethyl]-2- methyl-4-piperidinone (AstaTech), catalytic hydrogenation CD₃OD: δ 5.53 (m, 1H),2.63 (m, 1H), 2.40- 2.17 (br m, 8H), 0.96 (m, 12H) ND

293 (S)-1-[(S)-1-({6- [(Dimethylamino) methyl]perhydro- isoquinol-2-yl}carbonyl)-3- methylbutyl]-3- isobutyl-2- piperazinone tert-Butyl 6-hydroxy- decahydro- isoquinoline-2- carboxylate (Enamine BB), oxidationto ketone, Wittig reaction with Methyltriphenyl phosphonium bromide,hydroboration, oxidation to CDCl₃: δ 5.48 (t, 1H), 3.05 (m, 2H), 2.86(m, 2H), 2.22 (s, 6H), 0.84 (m, 12H) *+ aldehyde, reductive aminationwith Dimethylamine, BOC removal

294 (S)-1-[(S)-1-({(2S)- 2-Methyl-4-[(1- methyl-2- piperidyl)methyl]- 1-piperidyl}carbonyl)- 3-methylbutyl]-3- isobutyl-2- piperazinonetert-Butyl 2- (hydroxymethyl)- 1- piperidine- carboxylate (Combi-Blocks), Mitsunobu reaction with 1,3- Benzothiazole-2- thiol (Combi-Blocks), oxidation to CDCl₃: δ 5.37 (t, 1H), 4.21 (m, 1H), 3.84 (m, 1H),2.41 (s, 3H), 0.84 (m, 12H) *+ sulfone, Julia- Kocienski olefinationwith with (S)-1-[(S)-1- Phenylethyl]-2- methyl-4- piperidinone(AstaTech), BOC removal, reductive amination with Formaldehyde,catalytic hydrogenation

295 (S)-1-[(S)-1-({(2S)- 2-Methyl-4-[(1- methyl-2- pyrrolidinyl)methyl]-1- piperidyl}carbonyl)- 3-methylbutyl]-3- isobutyl-2- piperazinonetert-Butyl 2- (hydroxymethyl)- 1- pyrrolidine- carboxylate (TCIAmerica), Mitsunobu reaction with 1,3- Benzothiazole-2- thiol (Combi-Blocks), oxidation to sulfone, Julia- Kocienski CDCl₃: δ 5.37 (t, 1H),4.16 (m, 1H), 2.78 (m, 2H), 2.24 (s, 3H), 0.80 (m, 12H) *+ olefinationwith with (S)-1-[(S)-1- Phenylethyl]-2- methyl-4- piperidinone(AstaTech), BOC removal, reductive amination with Formaldehyde,catalytic hydrogenation

296 (S)-1-[(S)-1- ({(3aS,7aR,2′S)-5- Methyl-2′-methyl- 3a,4,5,6,7,7a-hexahydrospiro [indene-2,4′- piperidin]-1′- yl}carbonyl)-3-methylbutyl]-3- isobutyl-2- piperazinone (3S,4R)-3,4- Piperidinediol(HCL salt, AstaTech), reductive amination with Formaldehyde,ketalization with (S)-1-[(S)-1- Phenylethyl]-2- methyl-4- piperidinone(AstaTech), catalytic hydrogenation CDCl₃: δ 5.54 (m, 1H), 4.14 (m, 5H),2.25 (s, 3H), 0.92 (m, 15H) ND

297 (3S)-1-[(2S)-4- Methyl-1-oxo-1- [(3s,6s,8S)-8- methyl-3-(1H-pyrazol-1- ylmethyl)-1,5- dioxa-9- azaspiro[5.5] undecan-9- yl]pentan-2-yl]-3-(2- methylpropyl) piperazin-2-one (^(≠)), isomer Z (S)-1-[(S)-1-Phenylethyl]-2- methyl-4- piperidinone (AstaTech), ketalization with(2,2-Dimethyl- 1,3-dioxan-5- yl)methanol (Combi-Blocks), tosylation ofalcohol, separation off and Z isomer, CDCl₃: δ 7.46 (s, 1H), 7.36 (s,1H), 6.20 (s, 1H), 5.50 (t, 1H), 0.92 (m, 15H) *+ substitution oftosylate with 1H- Pyrazole, catalytic hydrogenation

298 (S)-1-[(S)-1-({(S)-8- Methyl-3-(1- methyl-2- piperidyl)-1,5-dioxa-9-aza-9- spiro[5.5]undecyl} carbonyl)-3- methylbutyl]-3-isobutyl-2- piperazinone 2-(1- Methylpiperidin- 2-yl)propane- 1,3-diol(Oakwood Chemical), ketalization with (S)-1-[(S)-1- Phenylethyl]-2-methyl-4- piperidinone (AstaTech), catalytic hydrogenation CD₃OD: δ5.58- 5.49 (m, 1H), 3.17-3.07 (m, 1H), 2.38 (s, 3H), 1.00-0.92 (m, 12H)++++

299 (S)-1-[(S)-1-({(10S)- 1- (Dimethylamino)- 10-methyl-7,14-dioxa-11-aza-11- dispiro[4.2.5.2] pentadecyl}carbonyl)-3-methylbutyl]-3- isobutyl-2- piperazinone, methanesulfonic acid saltMethyl 2- oxocydopentane carboxylate, alkylation with Benzyloxymethylchloride, reduction with LAH, catalytic hydrogenation, ketalization with(S)-1-[(S)-1- Phenylethyl]-2- methyl-4- piperidinone (AstaTech),mesylation of alcohol, CD₃OD: δ 5.60 5.48 (m, 1H), 4.16-4.05 (m, 2H),3.01-2.88 (m, 6H), 1.06- 0.94 (m, 12H) *+ substitution of mesylate withDimethylamine, catalytic hydrogenation

300 (S)-1-[(S)-1-({(2′S)- 7-Methyl-2′- methylspiro[2.4- dioxa-7-azabicyclo[3.3.0] octane-3,4′- piperidin]-1′- yl}carbonyl)-3-methylbutyl]-3- isobutyl-2- piperazinone cis-Pyrrolidine- 3,4-diol (HClsalt, Combi-Blocks), reductive amination with Formaldehyde, ketalizationwith (S)-1-[(S)-1- Phenylethyl]-2- methyl-4- piperidinone (AstaTech),catalytic hydrogenation CD₃OD: δ 5.56 (m, 1H), 4.76 (m, 1H), 4.68 (m,1H), 2.37 (s, 3H), 0.96 (m, 12H) ND

301 (S)-1-[(S)-1-({(S)-8- Methyl-3-(1H- pyrazol-1-yl)-1,5-dioxa-9-aza-9- spiro[5.5]undecyl} carbonyl)-3- methylbutyl]-3-isobutyl-2- piperazinone Glycerol, protection of primary alcohols withtert- Butyldimethylsilyl chloride, mesylation of secondary alcohol,substitution of mesylate with 1H-Pyrazole, TBDMS ether removal,ketalization with (S)-1-[(S)-1- Phenylethyl]-2- CDCl₃: δ 7.52 (b s, 1H),745 (b s, 1H), 6.26 (b s, 1H), 5.55 (m, 1H), 0.92 (m, 15H) *+ methyl-4-piperidinone (AstaTech), catalytic hydrogenation

302 (S)-1-[(S)-1-({(S)-3- [(Dimethylamino) methyl]-3,8- dimethyl-1,5-dioxa-9-aza-9- spiro[5.5]undecyl} carbonyl)-3- methylbutyl]-3-isobutyl-2- piperazinone 2- (Hydroxymethyl)- 2-methyl-1,3- propanediol(Combi-Blocks), ketalization with (S)-1-[(S)-1- Phenylethyl]-2-methyl-4- piperidinone (AstaTech), oxidation of alcohol to aldehyde,reductive CD₃OD: δ 5.54 (m, 1H), 4.58 (m, 2H), 2.34 (m, 6H), 1.52 (m,10H), 0.95 (m, 15H) ++++ amination with Dimethylamine, catalytichydrogenation

TABLE 3 Compounds made through Method B1 and B2 Characterisitic Ex. ¹HNMR Cmpd Precursor III signals Structure # name synthesis (300 MHz)Activity

136 (S)-1-[(S)-1-({4-[2-(1,2- Dimethylpropylamino)- 2-oxoethyl]-1-piperidyl}carbonyl)-3- methylbutyl]-3- isobutyl-2-piperazinone (B1)IIIb-Z = CHCH₂C(O)OCH₃ (Combi-Blocks), (B2) hydrolysis, amide couplingCD₃OD: δ 5.57 (m, 1H), 4.48 (t, 1H), 4.09 (m, 1H), 0.96 (m, 18H) ++

137 (1-{(S)-2-[(S)-3-Isobutyl- 2-oxo-1-piperazinyl]-4- methylvaleryl}-4-piperidyl)acetic acid (B1) IIIb-Z = CHCH₂C(O)O CH₂CH₃ (Combi- Blocks),(B2) hydrolysis CD₃OD: δ 5.48 (m, 1H), 4.39 (t, 1H), 2.61 (m, 2H), 1.62(m, 11H), 0.88 (m, 12H) +*

138 (S)-1-[(S)-1-{[4-(2- Aminoethyl)-1- piperidyl]carbonyl}-3-methylbutyl]-3- isobutyl-2-piperazinone (B1) IIIb-Z = CHCH₂ CH₂NHBOC(Combi-Blocks), (B2) BOC deprotection CD₃OD: δ 5.53 (m, 1H), 4.46 (t,1H), 2.99 (m, 2H), 1.68 (m, 10H), 0.97 (m, 12H) +++

139 (S)-1-{(S)-2-[4-(2- Aminoethyl)-1- piperidyl]-1-methyl-2-oxoethyl}-3-isobutyl-2- piperazinone (B1) IIIb-Z = CHCH₂ CH₂NHBOC(Combi-Blocks), (B2) BOC deprotection CD₃OD: δ 4.80 (m, 1H), 3.84 (d,1H), 2.36 (m, 2H), 0.75 (d, 3H), 0.36 (m, 6H) +*

140 (S)-1-[(S)-1-{[4-(2- Aminoethyl)-1- piperidyl]carbonyl}-3-methylbutyl]-3-methyl- 2-piperazinone (B1) IIIb-Z = CHCH₂ CH₂NHBOC(Combi-Blocks), (B2) BOC deprotection CD₃OD: δ 4.77 (m, 1H), 3.76 (d,1H), 2.27 (m, 2H), 0.88 (m, 3H), 0.24 (m, 6H) +*

141 (S)-1-[(S)-3-Methyl-1- {[4-({4-methyl-2.4- diazabicyclo[3.3.0]octa-1(5),2-dien-3- yl}methyl)-1- piperidyl]carbonyl}butyl]- 3-isobutyl-2-piperazinone Z = CHCH₂COOH (Combi-Blocks), amide coupling with2-aminocyclo- pentanol, DMP oxidation to ketone, imine formation withmethylamine using Ti(OiPr)₄, cyclization to imidazole by treatment withPCl₅ CD₃OD: δ 5.55 (m, 1H), 4.47 (t, 1H), 3.55 (s, 3H), 2.65 (m, 6H),2.49 (m, 2H), 0.95 (m, 12H) +++

142 (S)-1-[(S)-3-Methyl-1- {[4-(1-methyl-1H- imidazol-2-ylthio)-1-piperidyl]carbonyl}butyl]- 3-isobutyl-2- piperazinone Z = CHOH,Mitsunobu reaction with 1- methyl-1H- imidazole-2-thiol CD₃OD: δ 7.25(s, 1H), 7.06 (s, 1H), 5.53 (m, 1H), 3.75 (s, 3H), 0.95 (m, 12H) ++

143 (S)-1-{(S)-3-Methyl-1- [(4-phenoxy-1- piperidyl)carbonyl]butyl}-3-isobutyl-2- piperazinone Z = CHOH, Mitsunobu reaction with phenolCD₃OD: δ 7.27 (t, 2H), 7.01- 6.88 (br m, 3H), 5.59 (m, 1H), 4.63 (m,1H), 2.93 (m, 1H), 0.95 (m, 12H) ++

144 1-{(S)-2-[(S)-3-Isobutyl- 2-oxo-1-piperazinyl]-4- methylvaleryl}-4-piperidyl acetate Z = CHOH, acylation with acyl chloride CD₃OD: δ 5.57(m, 1H), 4.99 (m, 1H), 2.91 (m, 1H), 2.05 (d, 3H), 0.95 (m, 12H) +*

145 1-{(S)-2-[(S)-3-Isobutyl- 2-oxo-1-piperazinyl]-4- methylvaleryl}-4-piperidyl phenylacetate Z = CHOH, acylation with phenylacetyl chlorideCD₃OD: δ 7.40-7.21 (br m, 5H), 5.55 (m, 1H), 5.00 (m, 1H), 3.65 (d, 2H),2.90 (m, 1H), 0.95 (m, 12H) +*

146 (S)-1-[(S)-3-Methyl-1- ({4-[(3- pyridyloxy)methyl]-1-piperidyl}carbonyl)butyl]- 3-isobutyl-2- piperazinone Z = CHCH₂OH,Mitsunobu reaction with 3- Pyridinol CD₃OD: δ 8.23 (d, 1H), 8.12 (dd,1H), 7.43 (d, 1H), 7.35 (dd, 1H), 5.59 (m, 1H), 3.95 (d, 2H), 0.95 (m,12H) +*

147 (S)-1-[(S)-3-Methyl-1- ({4-[2-oxo-2-(1- pyrrolidinyl)ethyl]-1-piperidyl}carbonyl)butyl]- 3-isobutyl-2- piperazinone (B1) IIIb-Z =CHCH₂C(O)OCH₃ (Combi-Blocks), (B2) hydrolysis, amide coupling CD₃OD: δ5.57 (m, 1H), 3.51 (t, 2H), 2.31 (m, 2H), 0.97 (m, 12H) ++

148 (S)-1-[(S)-3-Methyl-1- {[4-(2-oxo-2- piperidinoethyl)-1-piperidyl]carbonyl}butyl]- 3-isobutyl-2- piperazinone (B1) IIIb-Z =CHCH₂C(O)OCH₃ (Combi-Blocks), (B2) hydrolysis, amide coupling CD₃OD: δ5.57 (m, 1H), 3.54 (m, 4H), 2.36 (m, 2H), 0.97 (m, 12H) ND

149 (S)-1-[(S)-3-Methyl-1- {[4-(2-morpholino-2- oxoethyl)-1-piperidyl]carbonyl}butyl]- 3-isobutyl-2- piperazinone (B1) IIIb-Z =CHCH₂C(O)OCH₃ (Combi-Blocks), (B2) hydrolysis, amide coupling CD₃OD: δ5.57 (m, 1H), 3.66 (m, 4H), 2.37 (m, 2H), 0.97 (m, 12H) +*

150 (S)-1-[(S)-3-Methyl-1- ({4-[2-(4-methyl-1- piperazinyl)-2-oxoethyl]-1- piperidyl}carbonyl)butyl]- 3-isobutyl-2- piperazinone (B1)IIIb-Z = CHCH₂C(O)OCH₃ (Combi-Blocks), (B2) hydrolysis, amide couplingCD₃OD: δ 5.57 (m, 1H), 3.61 (m, 4H), 2.33 (s, 3H), 0.97 (m, 12H) ++

151 (S)-1-[(S)-1-({4-[2- (Diethylamino)-2- oxoethyl]-1-piperidyl}carbonyl)-3- methylbutyl]-3- isobutyl-2-piperazinone (B1)IIIb-Z = CHCH₂C(O)OCH₃ (Combi-Blocks), (B2) hydrolysis, amide couplingCD₃OD: δ 5.57 (m, 1H), 3.41 (m, 6H), 2.33 (m, 2H), 0.97 (m, 12H) +*

152 (S)-1-[(S)-1-({4-[2- (Dibutylamino)-2- oxoethyl]-1-piperidyl}carbonyl)-3- methylbutyl]-3- isobutyl-2-piperazinone (B1)IIIb-Z = CHCH₂C(O)OCH₃ (Combi-Blocks), (B2) hydrolysis, amide couplingCD₃OD: δ 5.57 (m, 1H), 2.33 (m, 2H), 1.36 (m, 6H), 0.98 (m, 12H) +++

153 (S)-1-[(S)-1-[(4-{2-[N- Methyl(phenethyl)amino]- 2-oxoethyl}-1-piperidyl)carbonyl]-3- methylbutyl]-3- isobutyl-2-piperazinone (B1)IIIb-Z = CHCH₂C(O)OCH₃ (Combi-Blocks), (B2) hydrolysis, amide couplingCD₃OD: δ 7.34-7.18 (m, 5H), 5.55 (m, 1H), 3.63 (m, 2H), 0.97 (m, 12H) ++

154 (S)-1-[(S)-1-[(4-{[1- (Cyclopropylmethyl)- 1H-imidazol-2-yl]methyl}-1- piperidyl)carbonyl]-3- methylbutyl]-3-isobutyl-2-piperazinone B1) IIIb- Z = CHCH₂(1H- imidazole) (Enamine BB)(B2) N-alkylation CD₃OD: δ, 6.77 (d, 2H), 5.56 (q, 1H), 4.57 (t, 1H),0.9 (m, 12H), 0.67 (m 2H), 0.33 (m, 2H). ++

155 (S)-1-[(S)-1-({4-[(1- Ethyl-1H-imidazol-2- yl)methyl]-1-piperidyl}carbonyl)-3- methylbutyl]-3- isobutyl-2-piperazinone B1) IIIb-Z = CHCH₂(1H- imidazole) (Enamine BB) (B2) N-alkylation CD₃OD: δ, 6.95(S, 1H), 6.85 (s, 1H), 5.56 (q, 1H), 4.50 (t, 1H), 0.95, (m, 15H). +++

156 (S)-1-[(S)-1-({4-[(1- Isopropyl-1H-imidazol- 2-yl)methyl]-1-piperidyl}carbonyl)-3- methylbutyl]-3- isobutyl-2-piperazinone B1) IIIbZ = CHCH₂(1H- imidazole) (Enamine BB) (B2) N-alkylation CD₃OD: δ, 7.70(s, 1H), 7.50 (s, 1H), 5.56 (q, 1H), 4.50 (t, 1H), 1.5 (d, 6 H), 0.95(m, 12H). +++

157 (S)-1-[(S)-3-Methyl-1- ({4-[(1-propyl-1H- imidazol-2-yl)methyl]-1-piperidyl}carbonyl)butyl]- 3-isobutyl-2- piperazinone B1) IIIb- Z =CHCH₂(1H- imidazole) (Enamine BB) (B2) N-alkylation CD₃OD: δ 6.96 (S,1H), 6.86 (s, 1H), 5.55 (q, 1H)), 4.52 (t, 1H), 0.95, (m, 15H). +++

158 (S)-1-[(S)-1-({4-[(1- Isobutyl-1H-imidazol-2- yl)methyl]-1-piperidyl}carbonyl)-3- methylbutyl]-3- isobutyl-2-piperazinone B1) IIIb-Z = CHCH₂(1H- imidazole) (Enamine BB) (B2) N-alkylation CD₃OD: δ, 7.08(S, 1H), 6.86 (s, 1H), 5.60 (q, 1H), 4.50 (t, 1H), 0.90, (m, 18H). +++

159 (S)-1-[(S)-1-[(4-{[1-(3- Butenyl)-1H-imidazol-2- yl]methyl}-1-piperidyl)carbonyl]-3- methylbutyl]-3- isobutyl-2-piperazinone B1) IIIb-Z = CHCH₂(1H- imidazole) (Enamine BB) (B2) N-alkylation CD₃OD: δ, 6.80(m (1H), 6.75 (s, 1H), 5.56 (q, 1H) 4.45 (t, 1H), 0.94, (m, 12H). +++

160 (S)-1-[(S)-3-Methyl-1- ({4-[2-(1-methyl-1H- imidazol-2-yl)ethyl]-1-piperidyl}carbonyl)butyl]- 3-isobutyl-2- piperazinone B1) IIIb- Z =CHCH₂CH₂OH, (B2) oxidation to aldehyde, N- methyl imidazole construction(with ammonia, methylamine and glyoxal), tBOC removal CDCl3: δ, 6.90 (S,1H), 6.78 (s, 1H), 5.60 (q, 1H), 4.50 (t, 1H), 3.55 (s, 3H), 0.95, (m,13H). +++

161 (S)-1-[(S)-1-({4-[2-(N- Methyl-N- ethylamino)ethyl]-1-piperidyl}carbonyl)-3- methylbutyl]-3- isobutyl-2-piperazinone Z =CHCH₂CH₂OH, oxidation to aldehyde, reductive amination ¹H NMR (CD₃OD) δ0.98 (m, 12H), 1.23 (m, 5H), 1.71 (m, 10H), 2.86 (m, 4H), 4.48 (m, 1H),5.55 (m, 1H) ++++

162 (S)-1-[(S)-1-({4-[2-(N- Methyl-N- cyclopropylamino)ethyl]-1-piperidyl}carbonyl)- 3-methylbutyl]-3- isobutyl-2-piperazinone Z =CHCH₂CH₂OH, oxidation to aldehyde, reductive amination ¹H NMR (CD₃OD) δ0.48 (m, 2H), 0.97 (m, 12H), 1.09 (m, 2H), 1.64 (m, 12H), 2.36 (s, 3H),2.62 (m, 3H), 5.57 (m, 1H) ++++

163 (S)-1-[(S)-1-[(4-{2-[N- Methyl(isopropyl)amino] ethyl}-1-piperidyl)carbonyl]-3- methylbutyl]-3- isobutyl-2-piperazinone Z =CHCH₂CH₂OH, oxidation to aldehyde, reductive amination ¹H NMR (CD₃OD) δ0.96 (m, 12H), 1.15 (m, 5H), 2.34 (m, 2H), 4.08 (m, 1H), 4.49 (m, 1H),5.56 (m, 1H) ++

164 (S)-1-[(S)-3-Methyl-1- ({4-[(4- pyridyloxy)methyl]-1-piperidyl}carbonyl)butyl]- 3-isobutyl-2- piperazinone Z = CHCH₂OH,Mitsunobu reaction with 4- Pyridinol CD₃OD: δ 8.33 (d, 2H), 6.99 (d,2H), 5.58 (m, 1H), 3.98 (d, 2H), 0.95 (m, 12H) +++

165 (S)-1-[(S)-3-Methyl-1- ({4-[(2- pyrimidinyloxy)methyl]- 1-piperidyl}carbonyl)butyl]- 3-isobutyl-2- piperazinone Z = CHCH₂OH,Mitsunobu reaction with methyl 2- hydroxypyrimi- dine CD₃OD: δ 8.55 (d,2H), 7.09 (t, 1H), 5.58 (m, 1H), 4.28 (d, 2H), 0.95 (m, 12H) +*

166 (S)-1-[(S)-3-Methyl-1- ({4-[(o- tolyloxy)methyl]-1-piperidyl}carbonyl)butyl]- 3-isobutyl-2- piperazinone Z = CHCH₂OH,Mitsunobu reaction with o- cresol CD₃OD: δ 7.17-7.03 (br m, 2H),6.90-6.74 (br m, 2H), 5.59 (m, 1H), 3.85 (d, 2H), 2.18 (s, 3H), 0.95 (m,12H) +++

167 (S)-1-[(S)-3-Methyl-1- ({4-[(m- tolyloxy)methyl]-1-piperidyl}carbonyl)butyl]- 3-isobutyl-2- piperazinone Z = CHCH₂OH,Mitsunobu reaction with m- cresol CD₃OD: δ 7.11 (t, 1H), 6.77- 6.60 (brm, 3H), 5.58 (m, 1H), 3.82 (d, 2H), 2.29 (s, 3H), 0.95 (m, 12H) +++

168 (S)-1-[(S)-3-Methyl-1- ({4-[(p- tolyloxy)methyl]-1-piperidyl}carbonyl)butyl]- 3-isobutyl-2- piperazinone Z = CHCH₂OH,Mitsunobu reaction with p- cresol CD₃OD: δ 7.05 (d, 2H), 6.78 (d, 2H),5.58 (m, 1H), 3.80 (d, 2H), 2.24 (s, 3H), 0.95 (m, 12H) +++

169 (S)-1-[(S)-1-({4-[(o- Chlorophenoxy)methyl]- 1-piperidyl}carbonyl)-3-methylbutyl]-3- isobutyl-2-piperazinone Z = CHCH₂OH, Mitsunobureaction with o- chlorophenol CD₃OD: δ 7.34 (d, 1H), 7.24 (t, 1H), 7.04(d, 1H), 6.90 (t, 1H), 5.60 (m, 1H), 4.00- 3.87 (m, 2H), 0.96 (m, 12H)+++

170 (S)-1-[(S)-1-({4-[(p- Chlorophenoxy)methyl]- 1-piperidyl}carbonyl)-3-methylbutyl]-3- isobutyl-2-piperazinone Z = CHCH₂OH, Mitsunobureaction with p- chlorophenol CD₃OD: δ 7.23 (d, 2H), 6.89 (d, 2H), 5.59(m, 1H), 3.84 (d, 2H), 0.95 (m, 12H) +++

171 o-[(1-{(S)-2-[(S)-3- Isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyl)methoxy] benzonitrile Z = CHCH₂OH, Mitsunobureaction with salicylonitrile CD₃OD: δ 7.66-7.50 (br m, 2H), 7.15 (d,1H), 7.05 (t, 1H), 5.59 (m, 1H), 4.02 (d, 2H), 0.94 (m, 12H) +++

172 m-[(1-{(S)-2-[(S)-3- Isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyl)methoxy] benzonitrile Z = CHCH₂OH, Mitsunobureaction with m- hydroxybenzo- nitrile CD₃OD: δ 7.44 (t, 1H), 7.33- 7.19(br m, 3H), 5.59 (m, 1H), 3.91 (d, 2H), 0.95 (m, 12H) +++

173 (S)-1-[(S)-1-({4-[(o- Methoxyphenoxy) methyl]-1-piperidyl}carbonyl)-3- methylbutyl]-3- isobutyl-2-piperazinone Z =CHCH₂OH, Mitsunobu reaction with guaiacol CD₃OD: δ 6.98-6.78 (br m, 4H),5.58 (m, 1H), 3.94- 3.83 (br m, 2H), 3.81 (s, 3H), 0.95 (m, 12H) ++

174 (S)-1-[(S)-1-({4-[(m- Methoxyphenoxy) methyl]-1-piperidyl}carbonyl)-3- methylbutyl]-3- isobutyl-2-piperazinone Z =CHCH₂OH, Mitsunobu reaction with m- methoxyphenol CD₃OD: δ 7.14 (t, 1H),6.54- 6.42 (br m, 3H), 5.59 (m, 1H), 3.82 (d, 2H), 3.75 (s, 3H), 0.95(m, 12H) +++

175 (S)-1-[(S)-1-({4-[(p- Methoxyphenoxy) methyl]-1-piperidyl}carbonyl)-3- methylbutyl]-3- isobutyl-2-piperazinone Z =CHCH₂OH, Mitsunobu reaction with p- methoxyphenol CD₃OD: δ 6.91-6.77 (brm, 4H), 5.58 (m, 1H), 3.78 (d, 2H), 3.73 (s, 3H), 0.95 (m, 12H) +++

176 (S)-1-[(S)-1-[(4-{2- [(Benzyl)(1- ethylpropyl)amino]-2- oxoethyl}-1-piperidyl)carbonyl]-3- methylbutyl]-3- isobutyl-2-piperazinone (B1)IIIb-Z = CHCH₂C(O)OCH₃ (Combi-Blocks), (B2) hydrolysis, amide couplingCD₃OD: δ 7.41-7.18 (m, 5H), 5.57 (m, 1H), 0.97 (m, 12H), 0.90-0.78 (m,6H) +++

177 (S)-1-[(S)-1-{[4-(2- Benzylamino-2- oxoethyl)-1-piperidyl]carbonyl}-3- methylbutyl]-3- isobutyl-2-piperazinone (B1)IIIb-Z = CHCH₂C(O)OCH₃ (Combi-Blocks), (B2) hydrolysis, amide couplingCD₃OD: δ 5.57 (m, 1H), 4.38 (s, 2H), 2.20 (m, 2H), 0.96 (m, 12H) ++

178 (S)-1-[(S)-1-[(4-{2-[N- Methyl(benzyl)amino]- 2-oxoethyl}-1-piperidyl)carbonyl]-3- methylbutyl]-3- isobutyl-2-piperazinone (B1)IIIb-Z = CHCH₂C(O)OCH₃ (Combi-Blocks), (B2) hydrolysis, amide couplingCD₃OD: δ 5.57 (m, 1H), 4.64 (m, 2H), 2.42 (m, 2H), 0.96 (m, 12H) +++

179 (S)-1-[(S)-1-({4-[2- (Diallylamino)-2- oxoethyl]-1-piperidyl}carbonyl)-3- methylbutyl]-3- isobutyl-2-piperazinone (B1)IIIb-Z = CHCH₂C(O)OCH₃ (Combi-Blocks), (B2) hydrolysis, amide couplingCD₃OD: δ 5.93-5.72 (m, 2H), 5.57 (m, 1H), 2.35 (m, 2H), 0.97 (m, 12H) ++

180 (S)-1-[(S)-1-({4-[2-(1- Ethylpropylamino)-2- oxoethyl]-1-piperidyl}carbonyl)-3- methylbutyl]-3- isobutyl-2-piperazinone (B1)IIIb-Z = CHCH₂C(O)OCH₃ (Combi-Blocks), (B2) hydrolysis, amide couplingCD₃OD: δ 5.58 (m, 1H), 3.67 (m, 1H), 2.17 (m, 2H), 1.01- 0.87 (m, 18H)++

181 (S)-1-[(S)-1-({4-[2-(N- Ethyl-N- cyclohexylamino)-2- oxoethyl]-1-piperidyl}carbonyl)-3- methylbutyl]-3- isobutyl-2-piperazinone (B1)IIIb-Z = CHCH₂C(O)OCH₃ (Combi-Blocks), (B2) hydrolysis, amide couplingCD₃OD: δ 5.56 (m, 1H), 2.35 (m, 2H), 1.23-1.10 (m, 5H), 0.96 (m, 12H) ++

182 (S)-1-[(S)-1-[(4-{2-[N- Methyl(1- cyclopropylethyl)amino]-2-oxoethyl}-1- piperidyl)carbonyl]-3- methylbutyl]-3-isobutyl-2-piperazinone (B1) IIIb-Z = CHCH₂C(O)OCH₃ (Combi-Blocks), (B2)hydrolysis, amide coupling CD₃OD: δ 5.57 (m, 1H), 2.39- 2.26 (m, 2H),0.96 (m, 12H), 0.24-0.12 (m, 1H) +*

183 (S)-1-[(S)-1-[(4-{2-[N- Methyl(sec- butyl)amino]-2- oxoethyl}-1-piperidyl)carbonyl]-3- methylbutyl]-3- isobutyl-2-piperazinone (B1)IIIb-Z = CHCH₂C(O)OCH₃ (Combi-Blocks), (B2) hydrolysis, amide couplingCD₃OD: δ 5.57 (m, 1H), 2.36 (m, 2H), 0.97 (m, 12H), 0.92-0.81 (m, 3H) +*

184 (S)-1-[(S)-1-({4-[2-(1,3- Dimethylbutylamino)-2- oxoethyl]-1-piperidyl}carbonyl)-3- methylbutyl]-3- isobutyl-2-piperazinone (B1)IIIb-Z = CHCH₂C(O)OCH₃ (Combi-Blocks), (B2) hydrolysis, amide couplingCD₃OD: δ 5.56 (m, 1H), 4.01 (m, 1H), 2.11 (m, 2H), 0.95 (m, 18H) ++

185 (S)-1-[(S)-1-({4-[2- (Isopentylamino)-2- oxoethyl]-1-piperidyl}carbonyl)-3- methylbutyl]-3- isobutyl-2-piperazinone (B1)IIIb-Z = CHCH₂C(O)OCH₃ (Combi-Blocks), (B2) hydrolysis, amide couplingCD₃OD: δ 5.57 (m, 1H), 3.21 (t, 2H), 2.13 (m, 2H), 0.96 (m, 18H) ++

186 (S)-1-[(S)-1-[(4-{2-[N- Methyl(isopentyl)amino]- 2-oxoethyl}-1-piperidyl)carbonyl]-3- methylbutyl]-3- isobutyl-2-piperazinone (B1)IIIb-Z = CHCH₂C(O)OCH₃ (Combi-Blocks), (B2) hydrolysis, amide couplingCD₃OD: δ 5.58 (m, 1H), 3.40 (m, 4H), 2.34 (m, 2H), 0.97 (m, 18H) ++

187 (S)-1-[(S)-1-[(4-{2- [Bis(isopropyl)amino]- 2-oxoethyl}-1-piperidyl)carbonyl]-3- methylbutyl]-3- isobutyl-2-piperazinone (B1)IIIb-Z = CHCH₂C(O)OCH₃ (Combi-Blocks), (B2) hydrolysis, amide couplingCD₃OD: δ 5.57 (m, 1H), 2.31 (m, 2H), 1.39 (d, 6H), 0.96 (m, 12H) ++

188 (S)-1-[(S)-1-({4-[(p- Acetylphenoxy)methyl]-1-piperidyl}carbonyl)-3- methylbutyl]-3- isobutyl-2-piperazinone Z =CHCH₂OH, Mitsunobu reaction with 4′- hydroxyacetophen one CD₃OD: δ 7.96(d, 2H), 7.00 (d, 2H), 5.59 (m, 1H), 3.95 (d, 2H), 2.54 (s, 3H), 0.95(m, 12H) +++

189 Methyl p-[(1-{(S)-2-[(S)- 3-isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyl)methoxy] benzoate Z = CHCH₂OH, Mitsunobureaction with methyl p- hydroxybenzoate CD₃OD: δ 7.95 (d, 2H), 6.98 (d,2H), 5.59 (m, 1H), 3.94 (d, 2H), 3.86 (s, 3H), 0.95 (m, 12H) +++

190 {p-[(1-{(S)-2-[(S)-3- Isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyl)methoxy] phenyl}acetamide Z = CHCH₂OH,Mitsunobu reaction with 4- hydroxyphenyl- acetamide CD₃OD: δ 7.20 (d,2H), 6.86 (d, 2H), 5.58 (m, 1H), 3.84 (d, 2H), 3.43 (s, 2H), 0.95 (m,12H) ++

191 Methyl {p-[(1-{(S)-2- [(S)-3-isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyl)methoxy] phenyl}acetate Z = CHCH₂OH,Mitsunobu reaction with methyl 4- hydroxyphenyl- acetate CD₃OD: δ 7.15(d, 2H), 6.84 (d, 2H), 5.58 (m, 1H), 3.81 (d, 2 H), 3.64 (s, 3H), 3.54(s, 2H), 0.94 (m, 12H) +++

192 Methyl {p-[(1-{(S)-2- [(S)-4-acetyl-3-isobutyl-2-oxo-1-piperazinyl]-4- methylvaleryl}-4- piperidyl)methoxy]phenyl}acetate Z = CHCH₂OH, Mitsunobu reaction with methyl 4-hydroxyphenyl- acetate CDCl₃: δ 7.18 (d, 2H), 6.83 (d, 2H), 3.80 (d,2H), 3.68 (s, 3H), 3.56 (s, 3H), 0.97 (m, 12H) +++

193 p-[(1-{(S)-2-[(S)-3- Isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyl)methoxy] benzoic acid Z = CHCH₂OH, Mitsunobureaction with methyl p- hydroxybenzoate, ester hydrolysis CD₃OD: δ 7.89(d, 2H), 6.86 (d, 2H), 5.59 (m, 1H), 3.90 (d, 2H), 0.95 (m, 12H) +*

194 (S)-1-[(S)-1-[(4-{2-[N- Ethyl(isopropyl)amino]- 2-oxoethyl}-1-piperidyl)carbonyl]-3- methylbutyl]-3- isobutyl-2-piperazinone (B1)IIIb-Z = CHCH₂C(O)OCH₃ (Combi-Blocks), (B2) hydrolysis, amide couplingCD₃OD: δ 5.57 (m, 1H), 2.35 (m, 2H), 1.26-1.11 (m, 11H), 0.97 (m, 12H)++

195 Isopropyl (1-{(S)-2-[(S)- 3-isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyl)acetate (B1) IIIb-Z = CHCH₂C(O)OCH₃(Combi-Blocks), (B2) hydrolysis, ester coupling CD₃OD: δ 5.57 (m, 1H),2.27 (m, 2H), 1.24 (d, 6H), 0.96 (m, 12H) ++

196 Allyl (1-{(S)-2-[(S)-3- isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyl)acetate (B1) IIIb-Z = CHCH₂C(O)OCH₃(Combi-Blocks), (B2) hydrolysis, ester coupling CD₃OD: δ 6.03-5.88 (m,1H), 5.57 (m, 1H), 2.35 (m, 2H), 0.96 (m, 12H) +*

197 Cyclobutyl (1-{(S)-2-[(S)- 3-isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyl)acetate (B1) IIIb-Z = CHCH₂C(O)OCH₃(Combi-Blocks), (B2) hydrolysis, ester coupling CD₃OD: δ 5.57 (m, 1H),4.98 (m, 1H), 4.48 (t, 1H), 0.96 (m, 12H) ++

198 Isobutyl (1-{(S)-2-[(S)-3- isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyl)acetate (B1) IIIb-Z = CHCH₂C(O)OCH₃(Combi-Blocks), (B2) hydrolysis, ester coupling CD₃OD: δ 5.57 (m, 1H),3.88 (d, 2H), 2.32 (m, 2H), 0.97 (m, 18H) ++

199 1-Ethylbutyl (1-{(S)-2- [(S)-3-isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyl)acetate (B1) IIIb-Z = CHCH₂C(O)OCH₃(Combi-Blocks), (B2) hydrolysis, ester coupling CD₃OD: δ 5.57 (m, 1H),4.48 (t, 1H), 2.31 (m, 2H, 1.01- 0.87 (m, 18H) +++

200 sec-Butyl (1-{(S)-2-[(S)- 3-isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyl)acetate (B1) IIIb-Z = CHCH₂C(O)OCH₃(Combi-Blocks), (B2) hydrolysis, ester coupling CD₃OD: δ 5.58 (m, 1H),2.29 (m, 2H), 1.22 (d, 3H), 1.00- 0.89 (m, 15H) +++

201 1,2-Dimethylpropyl (1- {(S)-2-[(S)-3-isobutyl-2-oxo-1-piperazinyl]-4- methylvaleryl}-4- piperidyl)acetate (B1) IIIb-Z =CHCH₂C(O)OCH₃ (Combi-Blocks), (B2) hydrolysis, ester coupling CD₃OD: δ5.58 (m, 1H), 4.74 (m, 1H), 2.30 (m, 2H), 0.96 (m, 18H) +++

202 2-Methoxy-1- methylethyl (1-{(S)-2- [(S)-3-isobutyl-2-oxo-1-piperazinyl]-4- methylvaleryl}-4- piperidyl)acetate (B1) IIIb-Z =CHCH₂C(O)OCH₃ (Combi-Blocks), (B2) hydrolysis, ester coupling CD₃OD: δ5.58 (m, 1H), 5.09 (m, 1H), 3.36 (s, 3H), 0.97 (m, 12H) +*

203 2-Hydroxyethyl (1-{(S)- 2-[(S)-3-isobutyl-2-oxo- 1-piperazinyl]-4-methylvaleryl}-4- piperidyl)acetate (B1) IIIb-Z = CHCH₂C(O)OCH₃(Combi-Blocks), (B2) hydrolysis, ester coupling CD₃OD: δ 5.58 (m, 1H),4.35 (t, 2H), 2.37 (m, 2H), 0.97 (m, 12H) ++

204 Cyclopropylmethyl (1- {(S)-2-[(S)-3-isobutyl-2-oxo-1-piperazinyl]-4- methylvaleryl}-4- piperidyl)acetate (B1) IIIb-Z =CHCH₂C(O)OCH₃ (Combi-Blocks), (B2) hydrolysis, ester coupling CD₃OD: δ5.58 (m, 1H), 3.93 (d, 2H), 0.97 (m, 12H), 0.29 (m, 2H) ++

205 Cyclobutylmethyl (1- {(S)-2-[(S)-3-isobutyl-2- oxo-1-piperazinyl]-4-methylvaleryl}-4- piperidyl)acetate (B1) IIIb-Z = CHCH₂C(O)OCH₃(Combi-Blocks), (B2) hydrolysis, ester coupling CD₃OD: δ 5.58 (m, 1H),4.07 (d, 2H), 2.31 (m, 2H), 0.97 (m, 12H) ++

206 Cyclopentyl (1-{(S)-2- [(S)-3-isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyl)acetate (B1) IIIb-Z = CHCH₂C(O)OCH₃(Combi-Blocks), (B2) hydrolysis, ester coupling CD₃OD: δ 5.58 (m, 1H),5.16 (m, 1H), 2.27 (m, 2H), 0.97 (m, 12H) ++

207 Benzyl (1-{(S)-2-[(S)-3- isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyl)acetate (B1) IIIb-Z = CHCH₂C(O)OCH₃(Combi-Blocks), (B2) hydrolysis, ester coupling CD₃OD: δ 5.57 (m, 1H),5.13 (s, 2H), 2.36 (m, 2H), 0.96 (m, 12H) ++

208 2-Hydroxy-2- methylpropyl (1-{(S)-2- [(S)-3-isobutyl-2-oxo-1-piperazinyl]-4- methylvaleryl}-4- piperidyl)acetate (B1) IIIb-Z =CHCH₂C(O)OCH₃ (Combi-Blocks), (B2) hydrolysis, ester coupling CD₃OD: δ5.58 (m, 1H), 3.94 (s, 2H), 2.37 (m, 2H), 0.96 (m, 12H) +*

209 (4-Pyridyl)methyl (1- {(S)-2-[(S)-3-isobutyl-2-oxo-1-piperazinyl]-4- methylvaleryl}-4- piperidyl)acetate (B1) IIIb-Z =CHCH₂C(O)OCH₃ (Combi-Blocks), (B2) hydrolysis, ester coupling CD₃OD: δ8.55-8.47 (m, 2H), 7.43 (m, 2H), 5.56 (m, 1H), 0.96 (m, 12H) ++

210 Cyclohexyl (1-{(S)-2- [(S)-3-isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyl)acetate (B1) IIIb-Z = CHCH₂C(O)OCH₃(Combi-Blocks), (B2) hydrolysis, ester coupling CD₃OD: δ 5.58 (m, 1H),4.77 (m, 1H), 2.29 (m, 2H), 0.97 (m, 12H) +++

211 1-{(S)-2-[(S)-3-Isobutyl- 2-oxo-1-piperazinyl]-4- methylvaleryl}-4-piperidinecarboxylic acid (B1) IIIb-Z = CHC(O)OCH₃, (B2) hydrolysisCD₃OD: δ 5.53 (m, 1H), 4.46- 4.22 (br m, 1H), 2.31 (m, 1H), 0.89 (m,12H) +*

212 Isopentyl 1-{(S)-2-[(S)- 3-isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidinecarboxylate (B1) IIIb-Z = CHC(O)OCH₃, (B2)hydrolysis, ester coupling CD₃OD: δ 5.59 (m, 1H), 4.16 (m, 2H), 2.68 (m,1H), 0.97 (m, 18H) ++

213 (S)-1-[(S)-1-{[4-({m- [(Dimethylamino)methyl] phenoxy}methyl)-1-piperidyl]carbonyl}-3- methylbutyl]-3- isobutyl-2-piperazinone Z =CHCH₂OH, Mitsunobu reaction with m- hydroxybenzalde- hyde, reductiveamination with dimethylamine CD₃OD: δ 7.27 (t, 1H), 7.00- 6.86 (br m,3H), 5.58 (m, 1H), 3.88 (d, 2H), 3.68 (s, 2H), 2.41 (s, 6H), 0.95 (m,+++ 12H)

214 (S)-1-[(S)-1-{[4-({p- [(Dimethylamino)methyl] phenoxy}methyl)-1-piperidyl]carbonyl}-3- methylbutyl]-3- isobutyl-2-piperazinone Z =CHCH₂OH, Mitsunobu reaction with p- hydroxybenzalde- hyde, reductiveamination with dimethylamine CD₃OD: δ 7.21 (d, 2H), 6.88 (d, 2H), 5.59(m, 1H), 3.85 (d, 2H), 3.40 (s, 2H), 2.21 (s, 6H), 0.95 (m, 12H) +++

215 {p-[(1-{(S)-2-[(S)-3- Isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyl)methoxy] phenyl}acetic acid Z = CHCH₂OH,Mitsunobu reaction with methyl 4- hydroxyphenyl- acetate, esterhydrolysis CD₃OD: δ 7.20 (d, 2H), 6.81 (d, 2H), 5.58 (m, 1H), 3.83 (d,2H), 3.39 (s, 2H), 0.95 (m, 12H) +*

216 {p-[(1-{(S)-2-[(S)-4- Acetyl-3-isobutyl-2-oxo- 1-piperazinyl]-4-methylvaleryl}-4- piperidyl)methoxy] phenyl}acetic acid Z = CHCH₂OH,Mitsunobu reaction with methyl 4- hydroxyphenyl- acetate, esterhydrolysis CD₃OD: δ 7.20 (d, 2H), 6.81 (d, 2H), 5.58 (m, 1H), 5.04 (m,1H), 3.39 (s, 2H), 2.13 (s, 3H), 0.97 (m, 12H) +*

217 (S)-1-[(S)-1-{[4-({o- [(Dimethylamino)methyl] phenoxy}methyl)-1-piperidyl]carbonyl}-3- methylbutyl]-3- isobutyl-2-piperazinone Z =CHCH₂OH, tosylation with tosyl choride, substitution reaction withsalicylaldehyde, reductive amination with dimethylamine CD₃OD: δ7.42-7.30 (br m, 2H), 7.06 (d, 1H), 6.99 (t, 1H); 5.58 (m, 1H), 3.95 (m,4H), 2.60 (s, 6H), 0.95 (m, 12H) +++

218 3-Cyclopenten-1-yl 1- {(S)-2-[(S)-3-isobutyl-2-oxo-1-piperazinyl]-4- methylvaleryl}-4- piperidinecarboxylate (B1)IIIb-Z = CHC(O)OCH₃, (B2) hydrolysis, ester coupling CD₃OD: δ 5.74 (s,2H), 5.58 (m, 1H), 2.64 (m, 1H), 0.98 (m, 12H) ++

219 Cyclopropylmethyl 1- {(S)-2-[(S)-3-isobutyl-2- oxo-1-piperazinyl]-4-methylvaleryl}-4- piperidinecarboxylate (B1) IIIb-Z = CHC(O)OCH₃, (B2)hydrolysis, ester coupling CD₃OD: δ 5.60 (m, 1H), 2.70 (m, 1H), 0.98 (m,12H), 0.31 (m, 2H) +*

220 2-Cyclopentylethyl 1- {(S)-2-[(S)-3-isobutyl-2-oxo-1-piperazinyl]-4- methylvaleryl}-4- piperidinecarboxylate (B1)IIIb-Z = CHC(O)OCH₃, (B2) hydrolysis, ester coupling CD₃OD: δ 5.58 (m,1H), 4.13 (m, 2H), 2.67 (m, 1H), 0.97 (m, 12H) +*

221 2-(2- Methoxyethoxy)ethyl 1- {(S)-2-[(S)-3-isobutyl-2-oxo-1-piperazinyl]-4- methylvaleryl}-4- piperidinecarboxylate (B1)IIIb-Z = CHC(O)OCH₃, (B2) hydrolysis, ester coupling CD₃OD: δ 5.58 (m,1H), 3.37 (s, 3H), 2.71 (m, 1H), 0.97 (m, 12H) ND

222 (S)-1-[(S)-3-Methyl-1- ({4-[(3-oxo-4- indanyloxy)methyl]-1-piperidyl}carbonyl)butyl]- 3-isobutyl-2- piperazinone (B1) IIIb-Z =CHCH₂OH, (B2) Mitsunobu reaction CD₃OD: 5.60 (m, 1H), 3.87 (d, 2H), 2.63(d, 2H), 0.97 (m, 12H) ++

223 (S)-1-[(S)-1-({4-[(m- Chlorophenoxy)methyl]- 1-piperidyl}carbonyl)-3-methylbutyl]-3- isobutyl-2-piperazinone (B1) IIIb-Z = CHCH₂OH, (B2)Mitsunobu reaction CD₃OD: δ 6.95 (s, 1H), 5.60 (m, 1H), 3.87 (d, 2H),0.97 (m, 12H) +++

224 Methyl m-[(1-{(S)-2- [(S)-3-isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyl)methoxy] benzoate (B1) IIIb-Z = CHCH₂OH,(B2) Mitsunobu reaction CD₃OD: δ 7.54 (s, 1H), 5.60 (m, 1H), 3.92 (m,5H), 0.97 (m, 12H) +++

225 p-[(1-{(S)-2-[(S)-3- Isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyl)methoxy] benzamide (B1) IIIb-Z = CHCH₂OH,(B2) Mitsunobu reaction CD₃OD: δ 7.85 (d, 2H), 5.60 (m, 1H), 3.94 (d,2H), 0.97 (m, 12H) ++

226 (S)-1-[(S)-1-({4-[(m- Acetylphenoxy)methyl]-1-piperidyl}carbonyl)-3- methylbutyl]-3- isobutyl-2-piperazinone (B1)IIIb-Z = CHCH₂OH, (B2) Mitsunobu reaction CD₃OD: δ 5.60 (m, 1H), 3.94(d, 2H), 2.60 (s, 3H), 0.97 (m, 12H) +++

227 m-[(1-{(S)-2-[(S)-3- Isobutyl-2-oxo-1- piperazinyl]-4-methylvaleryl}-4- piperidyl)methoxy] benzoic acid (B1) IIIb-Z = CHCH₂OH,(B2) Mitsunobu reaction CD₃OD: δ 7.53 (m, 2H), 5.60 (m, 1H), 3.91 (d,2H), 0.96 (m, 12H) +*

228 Methyl m-[(1-{(S)-2- [(S)-4-acetyl-3-isobutyl-2-oxo-1-piperazinyl]-4- methylvaleryl}-4- piperidyl)methoxy] benzoate(B1) IIIb-Z = CHCH₂OH, (B2) Mitsunobu reaction CDCl₃: δ 5.71-5.51 (m,1H), 3.92 (s, 3H), 2.11 (m, 3H), 0.98 (m, 12H) +++

229 m-[(1-{(S)-2-[(S)-4- Acetyl-3-isobutyl-2-oxo- 1-piperazinyl]-4-methylvaleryl}-4- piperidyl)methoxy] benzoic acid (B1) IIIb-Z = CHCH₂OH,(B2) Mitsunobu reaction CD₃OD: δ 7.53 (m, 2H), 5.59 (m, 1H), 2.14 (m,3H), 0.98 (m, 12H) ND

230 (S)-1-[(S)-1-({3- [(Dimethylamino)methyl]- 1,5-dioxa-9-aza-9-spiro[5.5]undecyl} carbonyl)-3-methylbutyl]- 3- isobutyl-2-piperazinone(B1) IIIb-Z = C═O, (B2) ketalization using (2,2- dimethyl-1,3- dioxan-5-yl)methanol (Combi-Blocks), tosylation of alcohol, substitution oftosylate using HNMe₂ CD₃OD: δ 5.57 (m, 1H), 3.98 (d, 2H), 2.88 (m, 1H),2.36 (d, 2H), 2.26 (s, 6H), 0.95 (m, 12H) ++++

231 (S)-1-[(S)-3-methyl-1- ({3-[(1- pyrrolidinyl)methyl]-1,5-dioxa-9-aza-9- spiro[5.5]undecyl} carbonyl)butyl]-3- isobutyl-2-piperazinone (B1) IIIb-Z = C═O, (B2) ketalization using (2,2-dimethyl-1,3- dioxan-5- yl)methanol (Combi-Blocks), tosylation ofalcohol, substitution of tosylate using pyrrolidine CD₃OD: δ 5.57 (m,1H), 3.42 (d, 2H), 1.65 (m, 4H), 1.00 (m, 12H) ++++

303 {m-[(1-{(S)-2-[(S)-4- Acetyl-3-isobutyl-2-oxo- 1-piperazinyl]-4-methylvaleryl}-4- piperidyl)methoxy] phenyl}acetic acid (B1) IIIb-Z =CHCH₂OH (B2) Mitsunobu reaction with Methyl (m- hydroxyphenyl) acetate,ester hydrolysis CD₃OD: δ 7.14 (t, 1H), 5.58 (m, 1H), 2.13 (m, 3H), 0.98(m, 12H) +*

304 (S)-1-[(S)-1-({3-[(4- Ethyl-1- piperidyl)methyl]-1,5- dioxa-9-aza-9-spiro[5.5]undecyl} carbonyl)-3-methylbutyl]- 3-isobutyl-2-piperazinone(B1) IIIb-Z = C═O (Combi-Blocks) (B2) ketalization with (2,2-Dimethyl-1,3-dioxan-5- yl)methanol (Combi-Blocks), mesylation of alcohol,substitution of mesylate using 4- Ethylpiperidine (AstaTech) CD₃OD: δ5.59 (dd, 1H), 3.98 (br d, 2H), 2.33 (d, 2H), 1.01- 0.89 (m, 15H) ++++

305 (S)-1-[(S)-1-[(3-{[(R)-3- Methyl-1- piperidyl]methyl}-1,5-dioxa-9-aza-9- spiro[5.5]undecyl) carbonyl]-3-methylbutyl]-3-isobutyl-2-piperazinone (B1) IIIb-Z = C═O (Combi-Blocks) (B2)ketalization with (2,2-Dimethyl- 1,3-dioxan-5- yl)methanol(Combi-Blocks), mesylation of alcohol, substitution of mesylate using(R)- 3-Methylpiperidine (AstaTech) CD₃OD: δ 5.59 (m, 1H), 4.03- 3.93 (m,2H), 2.95- 2.80 9m, 3H), 2.40-2.33 (m, 2H) ++++

306 (S)-1-[(S)-1-({3-[(3,5- Dimethyl-1- piperidyl)methyl]-1,5-dioxa-9-aza-9- spiro[5.5]undecyl} carbonyl)-3-methylbutyl]-3-isobutyl-2-piperazinone (B1) IIIb-Z = C═O (Combi-Blocks) (B2)ketalization with (2,2-Dimethyl- 1,3-dioxan-5- yl)methanol(Combi-Blocks), mesylation of alcohol, substitution of mesylate using3,5- cis- Dimethylpiperidine (AstaTech) CD₃OD: δ 5.58 (dd, 1H), 2.34 (d,2H), 0.97 (m, 12H), 0.89 (d, 6H) ++++

307 (S)-1-[(S)-1-({3-[(3,5- Dimethyl-1- piperidyl)methyl]-1,5-dioxa-9-aza-9- spiro[5.5]undecyl} carbonyl)-3-methylbutyl]-3-isobutyl-4-methyl-2- piperazinone (B1) IIIb-Z = C═O (Combi-Blocks)(B2) ketalization with (2,2-Dimethyl- 1,3-dioxan-5- yl)methanol(Combi-Blocks), mesylation of alcohol, substitution of mesylate usingcis- 3,5- CDCl₃: δ 5.57 (m, 1H), 2.49 (m, 1H), 2.33 (s, 3H), 0.97- 0.79(m, 18H) ++++ Dimethylpiperidine (AstaTech)

308 (S)-1-[(S)-1-[(3-{(3- Azabicyclo[3.1.0]hex-3-yl)methyl}-1,5-dioxa-9- aza-9- spiro[5.5]undecyl)carbonyl]-3-methylbutyl]- 3-isobutyl-2-piperazinone (B1) IIIb-Z = C═O(Combi-Blocks) (B2) ketalization with (2,2-Dimethyl- 1,3-dioxan-5-yl)methanol (Combi-Blocks), mesylation of alcohol, substitution ofmesylate using 3- Azabicyclo[3.1.0] CD₃OD: δ 5.61-5.55 (m, 1H), 2.66 (m,1H), 0.97 (m, 12H), 0.40-0.31 (m, 1H) ++++ hexane (AstaTech)

309 (S)-1-[(S)-1-[(3-{(3- Azabicyclo[3.1.0]hex-3-yl)methyl}-1,5-dioxa-9- aza-9- spiro[5.5]undecyl)carbonyl]-3-methylbutyl]- 3-isobutyl-4-methyl-2- piperazinone (B1)IIIb-Z = C═O (Combi-Blocks) (B2) ketalization with (2,2-Dimethyl-1,3-dioxan-5- yl)methanol (Combi-Blocks), mesylation of alcohol,substitution of mesylate using 3- Azabicyclo[3.1.0] CDCl₃: δ 5.62-5.54(m, 1H), 2.34 (s, 3H), 0.98- 0.87 (m, 12H), 0.38-0.26 (m, 1H) ++++hexane (AstaTech)

310 (S)-1-[(S)-1-[(3-{(6-Aza- 6- spiro[2.5]octyl)methyl}-1,5-dioxa-9-aza-9- spiro[5.5]undecyl) carbonyl]-3-methylbutyl]-3-isobutyl-2-piperazinone (B1) IIIb-Z = C═O (Combi-Blocks) (B2)ketalization with (2,2-Dimethyl- 1,3-dioxan-5- yl)methanol(Combi-Blocks), mesylation of alcohol, substitution of mesylate using 6-CD₃OD: δ 5.62-5.56 (m, 1H), 2.43-2.37 (m, 2H), 0.97 (m, 12H), 0.31 (s,4H) ++++ Azaspiro[2.5] octane (AstaTech)

311 (S)-1-[(S)-1-({3-[(4,4- Difluoro-1- piperidyl)methyl]-1,5-dioxa-9-aza-9- spiro[5.5]undecyl} carbonyl)-3-methylbutyl]-3-isobutyl-2-piperazinone (B1) IIIb-Z = C═O (Combi-Blocks) (B2)ketalization with (2,2-Dimethyl 1,3-dioxan-5- yl)methanol(Combi-Blocks), mesylation of alcohol, substitution of mesylate using4,4 CD₃OD: δ 5.62-5.55 (m, 1H), 2.96-2.76 (m, 3H), 2.43 (d, 2H), 0.97(m, 12H) *+ Difluoropiperidine (AstaTech)

312 (S)-1-[(S)-1-[(3-{(6-Aza- 6- spiro[2.5]octyl)methyl}-1,5-dioxa-9-aza-9- spiro[5.5]undecyl) carbonyl]-3-methylbutyl]-3-isobutyl-4-methyl-2- piperazinone (B1) IIIb-Z = C═O (Combi-Blocks)(B2) ketalization with (2,2-Dimethyl- 1,3-dioxan-5- yl)methanol(Combi-Blocks), mesylation of alcohol, substitution of mesylate using 6-CDCl₃: δ 5.62-5.55 (m, 1H), 2.34 (s, 3H), 0.98- 0.87 (m, 12H), 0.26 (s,4H) ++++ Azaspiro[2.5]octane (AstaTech)

313 (S)-1-[(S)-1-({3-[(4,4- Difluoro-1- piperidyl)methyl]-1,5-dioxa-9-aza-9- spiro[5.5]undecyl} carbonyl)-3-methylbutyl]-3-isobutyl-4-methyl-2- piperazinone (B1) IIIb-Z = C═O (Combi-Blocks)(B2) ketalization with (2,2-Dimethyl- 1,3-dioxan-5- yl)methanol(Combi-Blocks), mesylation of alcohol, substitution of mesylate using4,4- Difluoropiperidine CDCl₃: δ 5.62-5.55 (m, 1H), 2.86-2.80 (m, 1H),2.35 (s, 3H), 0.98- 0.87 (m, 12H) ND (AstaTech)

314 (S)-1-[(S)-1-({(S)-8- Methyl-3- (morpholinomethyl)-1,5-dioxa-9-aza-9- spiro[5.5]undecyl} carbonyl)-3-methylbutyl]-3-isobutyl-2-piperazinone (B1) IIIb-Z = C═O (HCl salt, AstaTech) (B2)ketalization with (2,2-Dimethyl- 1,3-dioxan-5- yl)methanol(Combi-Blocks), mesylation of alcohol, substitution of mesylate usingMorpholine CD₃OD: δ 5.54 (m, 1H), 3.68 (m, 6H), 2.55-1.87 (br m, 9H),0.95 (m, 12H) ++++

315 (S)-1-[(S)-1-({(S)-3-[(4,4- Difluoro-1- piperidyl)methyl]-8-methyl-1,5-dioxa-9-aza- 9- spiro[5.5]undecyl} carbonyl)-3-methylbutyl]-3-isobutyl-2-piperazinone (B1) IIIb-Z = C═O (HCl salt, AstaTech) (B2)ketalization with (2,2-Dimethyl- 1,3-dioxan-5- yl)methanol(Combi-Blocks), mesylation of alcohol, substitution of mesylate using4,4- Difluoropiperidine CD₃OD: δ 5.54 (m, 1H), 4.11- 3.59 (br m, 5H),3.05-2.79 (br m, 2H), 0.95 (m, 12H) ++++ (AstaTech)

316 (S)-1-[(S)-1-{[(S)-3-{(6- Aza-6- spiro[2.5]octyl)methyl}-8-methyl-1,5-dioxa-9- aza-9- spiro[5.5]undecyl]carbonyl}-3-methylbutyl]- 3-isobutyl-2-piperazinone (B1) IIIb-Z = C═O(HCl salt, AstaTech) (B2) ketalization with (2,2-Dimethyl- 1,3-dioxan-5-yl)methanol (Combi-Blocks), mesylation of alcohol, substitution ofmesylate using 6- Azaspiro[2.5]octane CD₃OD: δ 5.55 (m, 1H), 4.09- 3.83(br m, 2H), 2.61-1.88 (br m, 9 H), 0.95 (m, 12H), 0.29 (s, 4H) ++++(AstaTech)

317 (S)-1-[(S)-1-({(S)-3-[(2,5- Dihydro-1H-pyrrol-1-yl)methyl]-8-methyl- 1,5-dioxa-9-aza-9- spiro[5.5]undecyl}carbonyl)-3-methylbutyl]- 3-isobutyl-2-piperazinone (B1) IIIb-Z = C═O(HCl salt, AstaTech) (B2) ketalization with (2,2-Dimethyl- 1,3-dioxan-5-yl)methanol (Combi-Blocks), mesylation of alcohol, substitution ofmesylate using 2,5- Dihydro-1H- pyrrole (AstaTech) CD₃OD: δ 5.81 (s,2H), 5.52 (m, 1H), 4.12-3.89 (br m, 2H), 0.95 (m, 12H) ++++

318 (S)-1-[(S)-1-({(S)-3-[(1- Azetidinyl)methyl]-8-methyl-1,5-dioxa-9-aza- 9- spiro[5.5]undecyl} carbonyl)-3-methylbutyl]-3-isobutyl-2-piperazinone (B1) IIIb-Z = C═O (HCl salt, AstaTech) (B2)ketalization with (2,2-Dimethyl- 1,3-dioxan-5- yl)methanol(Combi-Blocks), mesylation of alcohol, substitution of mesylate usingAzetidine CD₃OD: δ 5.52 (m, 1H), 2.59- 1.97 (br m, 6H), 1.91-1.42 (br m,9H); 0.95 (m, 12H) ++++

319 (S)-1-[(S)-1-({(S)-3- [(3,3-Difluoro-1- pyrrolidinyl)methyl]-8-methyl-1,5-dioxa-9-aza- 9- spiro[5.5]undecyl} carbonyl)-3-methylbutyl]-3-isobutyl-2-piperazinone (B1) IIIb-Z = C═O (HCl salt, AstaTech) (B2)ketalization with (2,2-Dimethyl- 1,3-dioxan-5- yl)methanol(Combi-Blocks), mesylation of alcohol, substitution of mesylate using3,3- Difluoropyrrolidine (AstaTech) CD₃OD: δ 5.53 (m, 1H), 4.10- 3.88(br m, 2H), 3.87-3.60 (br m, 5H); 0.95 (m, 12H) ++++

All starting materials for precursor II and III have been obtained fromSigma-Aldrich unless otherwise noted in Table 2 and 3 above.

The biological properties of compounds were investigated by way of theexperimental protocols described below:

Colony Formation Assay (CFA)

Cell Culture:

CaSki cells were obtained from CLS GmbH, Eppelheim, Germany (cat.300145) and subcultured in ready-to-use RPMI1640 Media (CLS GmbH cat.820700) after addition of “Antibiotic Antimycotic Solution”(Sigma-Aldrich, St Louis, USA, cat. A5955) at 1:100 dilution. CaSkicells were expanded and aliquots kept frozen in liquid nitrogenaccording to manufacturer's instructions. Once thawed, aliquots werepassaged every second or third day at a seed density of 20′000cells/cm²; and used for a maximum of twenty passages.

Preparation of the Cells for CFA:

Cell culture flasks were rinsed twice with Ca++/Mg++-freePhosphate-Buffered Saline (DPBS, CLS GmbH cat. 860015) and incubatedwith Accutase (CLS GmbH cat. 830100) for 15 min at 37° C. Cells wereresuspended in a four-fold volume of ready-to use RPMI, centrifuged at300 g for 10 minutes, the supernatant discarded and the cellsresuspended in ready-to-use RPMI1640 by pipetting up and down ten timeswith a serological pipette. Cell density was determined with a Via-1Cassette (Chemometec, Allerod, Denmark) on a Nucleocounter NC 3000(Chemometec). The required amount of cells was first diluted 1:10 inready-to-use RPMI; cells pipetted five times up-down with a serologicalpipette; and the 1:10 solution added to the final volume needed for thewhole assay setup. Cells were mixed again by pipetting up and downtwenty times with a serological pipette. The final cell density was 70cells/ml.

Seeding:

Cells were seeded column-wise in 6-well plates, while triplicates weretreated row-wise. Three ml cell suspension solution (210 cells) wereadded per well.

Treatment:

Compound stock solutions were prepared at a concentration of 30 mM in50% DMSO/50% water; and diluted in the same solution so that the volumeadded to the wells was of 51l and the final DMSO well concentration0.08%. Untreated cells (negative controls) were incubated in a) mediumonly; and b) 0.08% DMSO. Test performance was monitored by a standardtreatment with a fixed concentration of a reference compound (10 MCompound 57) that resulted in ˜80-90% inhibition of colony formation.Tests showing less than 75% or more than 95% inhibition were repeated.The plates were swirled gently after addition of the compounds and thecells incubated for 14 days at 37° C. Culture incubation solutions werereplaced after one week.

Staining:

Colonies were washed twice with ice-cold DPBS and fixed on ice with 1 mlice-cold 10% methanol solution for 30 min. The methanol solution wasremoved and colonies incubated with 0.1% Crystal Violet/DBPS for 20 minat room temperature. The wells were rinsed with water at roomtemperature, let dry and colonies were counted. Compounds e.g.,compounds of Table 2 and 3 were classified as follows:

-   -   ++++ more than 90% inhibition of colony formation at a        concentration of 6 μM    -   +++ more than 90% inhibition of colony formation at a        concentration of 50 μM    -   ++ more than 50% inhibition of colony formation at a        concentration of 50 μM    -   +* greater than 0% but less than or equal to 50% inhibition of        colony formation at a concentration of 50 μM    -   *+ greater than 0% but less than or equal to 50% inhibition of        colony formation at a concentration of 0.7 μM    -   ND activity not detectable at 0.7 μM in this assay

Tumor Growth Inhibition in a Patient-Derived Xenograft Model of Head andNeck Cancer

NMRI nude mice bearing HN11873 subcutaneous tumors (ExperimentalPharmacology and Oncology Berlin Buch GmbH, Berlin, Germany) weretreated p.o. BID with either vehicle (control) or 30 mg/kg test compound(S)-1-[(S)-1-({4-[(1H-Imidazol-2-yl)methyl]-1-piperidyl)}carbonyl)-3-methylbutyl]-3-isobutyl-2-piperazinone.The test compound was dissolved in 0.5% methylcellulose with tween 80.Treatment started at a mean tumor volume of 100 mm³ at study day 17. Theexperiment was finished at day 58 of the study because of large tumorsin group A and unchanged outcome. Tumor diameters were determined twiceweekly. Statistical analysis was performed with the software Graph PadPrism, Vers. 5.02 by using 2-Way-ANOVA with Bonferroni posttest. FIG. 1shows tumor growth inhibition for the vehicle and the test compound.

Example 320: Colony Formation Assay (CFA) with a Cervical Cancer CellLine

Cell Culture.

CaSki cells (cervical cancer) were obtained from CLS GmbH, Eppelheim,Germany (cat#300145) and subcultured in ready-to-use RPMI1640 Media(CLS#820700) after addition of “Antibiotic Antimycotic Solution”(Sigma-Aldrich, St Louis, USA) at 1:100 dilution. The cells wereexpanded, and aliquots kept frozen in liquid nitrogen according tomanufacturer's instructions; tested for mycoplasma contamination andgenotyped (Microsynth AG, Balgach, Switzerland). Once thawed, aliquotswere passaged every second or third day at a seed density of 20′000cells/cm²; and used for a maximum of twenty passages. For passaging,cell culture flasks were rinsed twice with Ca++/Mg++-freePhosphate-Buffered Saline (DPBS, CLS#860015) and incubated with Accutase(CLS#830100) for 15 min at 37° C. Cells were resuspended in a four-foldvolume of ready-to-use RPMI, centrifuged at 300 g for ten minutes, thesupernatant discarded and the cells resuspended in ready-to-use RPMI1640by pipetting up and down five times with a serological pipette. Celldensity was determined with a Via-1 Cassette (Chemometec, Allerod,Denmark) on a Nucleocounter NC 3000 (Chemometec). Where not stated,consumables and chemicals were purchased from well-known suppliers.

Preparation of the Cells for CFA.

Cell culture flasks were rinsed twice with DPBS and incubated withAccutase for 15 min at 37° C. Cells were resuspended in a four-foldvolume of ready-to use RPMI, centrifuged at 300 g for ten minutes, thesupernatant discarded and the cells resuspended in ready-to-use RPMI1640by pipetting up and down ten times with a serological pipette. Celldensity was determined with a Via-1 Cassette on a Nucleocounter NC 3000.The required amount of cells was first diluted 1:10 in ready-to-useRPMI; cells pipetted five times up-down with a serological pipette; andthe 1:10 solution added to the final volume needed for the whole assaysetup. Cells were mixed again by pipetting up and down twenty times witha serological pipette. The cell density used for the experiment was of140 cells/ml.

Seeding.

Cells were seeded row-wise in 12-well plates, while triplicates weretreated column-wise (i.e. all the first rows were seeded first, then thesecond rows, and finally the third rows). One and a half ml cellsuspension solution (a total of 210 cells) were added per well.

Treatment.

Compound stock solutions were prepared at a concentration of 30 mM in50% DMSO/50% water; and diluted in the same solution so that the volumeadded to the wells was of 2.5 μl and the final DMSO well concentrationof 0.08%. Untreated cells (negative controls) were incubated in a)medium only; and b) 0.08% DMSO. Test performance was monitored by astandard treatment with a fixed concentration of a reference compoundthat resulted in ˜80-90% inhibition of colony formation. The plates wereswirled gently after addition of the compounds and the cells incubatedfor nine days at 37° C. Culture incubation solutions were replaced afterfive days.

Staining.

Colonies were washed twice with ice-cold DPBS and fixed on ice with 1 mlice-cold 10% methanol solution for 30 min. The methanol solution wasremoved and colonies incubated with 0.1% Crystal Violet/DBPS for 20 minat room temperature. The wells were rinsed consecutively with 1.5, 1,and 0.5 ml water at room temperature and let dry.

Destaining and Data Evaluation.

Colony-bound crystal violet was solubilized in 500 μl 10% Acetic Acid.Plates were shaked for 30 sec and the acetic acid solution wastransferred to a 2 ml well in a 96-deep-well plate. Five-hundredmicroliter 10% acetic acid were added again to each well of the 12-wellplates, the plates shaken for 30 sec and the acetic acid transferred tothe same well of the 96-deep-well plate, mixed well and 100 μltransferred to a clear-bottom 96-Well plate. Absorbance was measured at600 nm with a SpectraMax M2e reader (Molecular Devices, Sunnyvale,Calif., USA). Percentage of colony formation was calculated from theaverage of the well triplicates compared to the untreated DMSO controlsafter subtraction of blank values. Blanks were obtained from wellsincubated for nine days with ready-to-use RPMI1640 only and processedthe same way as colony-containing wells. A typical result is shown inTABLE 4 for four cell lines and four different compounds.

TABLE 4 Shows the GI50 (50% growth inhibition) concentrations (nM =nmol/lt) for Compound 258; Compound 287; Compound 279; Compound 253; andCompound 284, in a 9-day colony survival assay of cancer cell linesderived from prostate (PC3); lung (A549); cervix (CaSki); and colon(HCT116). Compound PC3 A549 CaSki HCT116 Compound 258 3 5 2 1.5 Compound287 7 20 13 1.5 Compound 279 1.5 5 4 1 Compound 253 4 7 4.5 2 Compound284 3 10 6 1.5

Example 321: Cell Proliferation Screening with a Sixty-Seven Cancer CellLine Panel

For screening using a proliferation assay, the cells used were culturedat 37° C. with 5% CO2, except for those being cultured with L-15 medium(37° C. and 100% air, TABLE 7). Compound stock solutions (10 mM) weremade in sterile water, aliquoted and stored at room temperature.Cisplatin was used as reference Control. Plastic consumables, culturemedia and supplements were purchased from well-known suppliers (TABLE8).

Cell Seeding (Day −1).

When necessary, cells were trypsinized using standard methods (see e.g.example 01). Cells were collected and resuspended in 5-6 mL ofappropriate culture medium, counted and diluted to the needed density.Fifty-four μl (microliter) cells were seeded per well in a 384-wellplate. Extra four wells per cell line were seeded on an additional platefor Day 0 reading (baseline cell density). Cells were incubated at 37°C. overnight.

Compound Treatment and Day 0 Reading (Day 0).

Tenfold final concentration of test compounds and Cisplatin wereprepared in cell culture media (work dilutions). Six μl of work dilutionsolutions were dispensed into the corresponding wells in 384-well platesto bring the total volume up to 60 μl. Conditions were tested intriplicate. The plates were then incubated at 37° C. for five days. Forthe day 0 reading, 30 μl of CTG and 6 μl cell culture medium were addedto the day 0 plates, contents mixed for 2 min on a plate shaker, and theplates incubated for 10 min at room temperature in the dark.Luminescence was recorded on an EnVision Multi Label Reader (2104-0010A,PerkinElmer, USA).

Endpoint CTG Reading (Day 5).

The amounts of cells in the plates was determined by endpoint CTG-test.Thirty μl of CTG were added to the 60 μl of cell culture per well,contents mixed for 2 min on a plate shaker, and the plates incubated for10 min at room temperature in the dark. Luminescence was recorded on anEnVision Multi Label Reader.

Data Analysis.

Fifty percent growth inhibition concentrations (GI50) were calculatedbased on percentage of control data (untreated cells) from each cellline (TABLE 5 (this example) and TABLE 6). Curves were fitted using anonlinear regression model with a sigmoidal dose response. Examples ofobtained curves are depicted in FIG. 2A-2F.

TABLE 5 Compound 258 GI50 for sixty-seven tested cell lines. Shows theGI50 (50% growth inhibition) concentration (nM = nmol/lt) for Compound258 in a 5-day cell proliferation assay of 67 cancer cell lines derivedfrom 15 different tissues/organs. Cells with a value “>10′000” mean thatGI50 is higher than the highest tested concentration (10 μM). GI50 TumorType Cell Line (nM) Lymphoma Granta-519 38 KARPAS-422 48 KARPAS-299  5Ramos 27 Daudi 80 Raji 28 Leukemia MOLM-13  4 HL-60  5 Kasumi-1 19Jurkat 18 MOLT-4  9 K562 17 U937 22 HS-5  5 Brain/Nerves H4 11 SF268 30Breast MCF7 55 BT-20 15 BT474 72 SK-BR-3 12 AU565  3 Cervix CaSki 35SiHa 52 MS751 51 DoTc2 4510 14 HT-3 330  Ovary OVCAR-3 44 OVCAR-4 12Colorectal Caco-2 10 HCT116  5 HT-29  4 SW480 22 SW48  9 SW948 10 SW620 4 Stomach/Gastric MKN-45  4 IM95m  4 MKN-1  2 HS 746.T  8 SNU-16 13SNU-5  4 Kidney 786-O 28 Caki 2 14 Liver HEP-3B 23 Hep G2  6 HUH-7 10Lung A549 10 HCC4006  8 H460 11 HCC2935 >10′000    MRC-5 12 OesophagusKYSE-150 11 KYSE-270 44 Pancreas MIA PaCa-2 11 PANC-1 22 ProstateLNCaP-FGC  2 DU145  7 22RV1  9 PC-3 13 RPWE-1  4 VCAP 128  Skin WM-266-441 SK-MEL28 50 SK-MEL5 51 A375  6 Malme-3M >10′000    HDFA >10′000   (fibroblast)

TABLE 6 Cell proliferation GI50 (nM) of Compound 279, Compound 258 andCompound 284, Shows the GI50 (50% growth inhibition) concentration (nM =nmol/lt) for Compound 258; Compound 279; and Compound 284 in a 5-daycell proliferation assay of twelve cancer cell lines derived from sixdifferent tissues/organs. Cells with a value “>10′000” mean that GI50 ishigher than the highest tested concentration (10 μM). Compound CompoundCompound Tissue/Organ Cell line 279 258 284 Skin (fibroblast)HDFA >10′000     >10′000     >10′000    Colorectal HCT 116 3 5  9 HS746.T 5 8 14 HT-29 4 4  7 SW48 6 9 14 SW620 2 4  7 SW948 3 10  12Leukemia HS-5 3 5 10 Lung MRC-5 10  12  24 Prostate RWPE-1 3 4 10Stomach SNU-16 10  13  22 SNU-5 3 4  6

TABLE 7 Example cell culture media for human cancer cell lines used inthe proliferation assay. Tissue Origin/ Cell Line Growth propertyCulture medium HL-60 Blood/Suspension RPMI-1640 + 10% FBS Kasumi-1Blood/Suspension RPMI-1640 + 20% FBS Granta-519 Blood/Suspension DMEM +10% FBS H4 Brain&Nerves/ RPMI1640 + 10% FBS + Adherent Glutamax BT-20Breast/Adherent MEM + 0.01 mM NEAA + 10% FBS MCF7 Breast/Adherent MEM +0.01 mM NEAA + 10% FBS + 10 μg/mL Insulin SK-BR-3 Breast/AdherentMcCoy's 5a + 10% FBS Caco-2 Colorectum/Adherent MEM + 0.01 mM NEAA + 10%FBS SW480 Colorectum/Adherent L-15 + 10% FBS KYSE-270 Esophagus/AdherentRPMI-1640/F12 + 2% FBS Caki2 Kidney/Adherent McCoy's 5a + 10% FBS A549Lung/Adherent Ham's F12K + 10% FBS OVCAR3 Ovary/Adherent RPMI1640 + 20%FBS + 10 μg/ml Insulin MIA PaCa-2 Pancreas/Adherent DMEM + 10% FBS +2.5% HS

TABLE 8 Reagent suppliers. Reagent Supplier Cat# F-12K GIBCO 21127022RPMI1640 GIBCO C22400500BT DMEM Hyclone SH30243.01 McCoy's 5A GIBCO12330-031 MEM Hyclone SH30024.01 IMDM GIBCO 31980-030 FBS ExCell FND500L-15 GIBCO 11415-064 NEAA GIBCO 11140-050 L-Glutamine 200 mM GIBCO25030-081 Trypsin (0.25%) Hyclone SH30042.02 Insulin Sigma 11070-73-8GlutaMAX GIBCO 35050-061 DMSO Amresco 0231 384 well cell culture plateCorning 3765 CellTiter-Glo Luminescent Cell Promega G7573 Viability kit(CTG)

Example 322: Castration Resistant Prostate Cancer Patient-DerivedXenograft

NSG NOD.Cg-PrkdcscidIj2rgtmIWjl/SzJ mice (6-8 weeks of age) wereinjected with patient-derived castration-resistant prostate tumor cells(model #PR6511, Crown Bioscience UK Ltd Hillcrest, OsgathorpeLeicestershire, UK). The cells were inoculated subcutaneously into theleft flank of 40 male NSG mice. When tumors reached a mean volume ofapproximately 100 mm³ (i.e. 100 mm³+/−54 mm³, FIG. 3), mice wererandomly assigned to five treatment groups of each eight mice (TABLE 9).Body weights were measured three times weekly prior to the initiation ofdosing and daily thereafter. Tumor burden was assessed by calipermeasurement three times weekly. Dosing breaks were applied whentolerability issues arose (body weight loss >10%). Upon completion ofthe scheduled dosing phase at day 57, tumor outgrowth was monitored forgroups 3, 4 and 5 up to study day 77. Groups 1 and 2 were terminated onstudy day 57. Results of the experiment are shown in TABLES 10 and 11;and FIGS. 3 and 4. The experiment was performed in the Crown BioscienceLtd. testing facility (Crown Bioscience UK Ltd Hillcrest, DodgefordLane, Osgathorpe Leicestershire LE12 9TE, UK).

TABLE 9 CRPC PDX mice treatment group assignment. Treatment GroupCompound Formulation schedule 1 Vehicle 0.5% Methylcellulose + p.o. QD0.1% Tween-80 2 Enzalutamide 1% w/v Carboxymethyl p.o. QD, 30 Cellulose(CMC; low mg/kg viscosity); 0.1% v/v Tween-80; 5% v/v DMSO 3 Compound258 0.5% Methylcellulose + p.o. QD, 10 0.1% Tween-80 mg/kg, 3 mg/kg fromday 51 on 4 Compound 258 0.5% Methylcellulose + p.o. QD, 6 0.1% Tween-80mg/kg 5 Compound 284 0.5% Methylcellulose + p.o. QD, 6 0.1% Tween-80mg/kg p.o. = oral administration (oral gavage). QD = once a day. v/v =volume/volume

TABLE 10 CRPC PDX RESPONSE SUMMARY. Treatment (group) PR CR TFS Vehicle(1) 0 0 0 Enzalutamide (2) 0 0 0 Compound 258 10 mg/kg (3) 2 4 3Compound 258 6 mg/kg (4) 2 3 3 Compound 284 6 mg/kg (5) 2 3 3 PR(partial regression) = number of mice presenting a tumor size ≤50% lowerthan initial tumor size during at least 3 consecutive measurements and≥13.5 mm³ for one or more of these three measurements; CR (completeregression) = number of mice presenting ≤13.5 mm³ tumor size during atleast 3 consecutive measurements; TFS (Tumor Free Survival) = number ofcomplete regressions recorded up to Group Day End. Animals were scoredonly once during the study for a PR or CR event and only as CR if bothPR and CR criteria were satisfied.

TABLE 11 CRPC PDX TWO-WAY ANOVA (tumor size at the end of the study).Compound 258 Compound 258 Compound 284 vs. Enzalutamide 10 mg/kg 6 mg/kg6 mg/kg Vehicle n.s. p < 0.0001 p < 0.0001 p < 0.0001 Enzalutamide — p <0.0001 p < 0.0001 p < 0.0001 Compound 258 — — n.s. n.s. 10 mg/kgCompound 258 — — — n.s. 6 mg/kg Compound 284 — — — — 6 mg/kg n.s. = notsignificant.

Example 323: Cell-Derived Xenograft Mouse Model for Prostate Cancer

Male BALB/c nude mice (7-9 weeks of age) were injected withhormone-refractory DU-145 human prostate cancer cells. The cells wereinoculated subcutaneously into the left flank of 48 mice. When tumorsreached a mean volume of approximately 105 mm³, mice were randomlyassigned to eight treatment groups of each six mice (TABLE 12). Bodyweights were measured three times weekly prior to the initiation ofdosing and daily thereafter. Tumor burden was assessed by calipermeasurement three times weekly. Dosing breaks were applied whentolerability issues arose (body weight loss >10%). The study wasterminated 4 weeks post first dosing. Results of the experiment areshown in TABLE 13, FIG. 5 and FIG. 6. The experiment was performed inthe Crown Bioscience Ltd. (Bejing) testing facility (Ground Floor, LightMuller Building, Changping Sector of Zhongguancun Scientific Park, No.21 Huoju Road, Changping District, Bejing, CHN).

TABLE 12 DU-145 CDX mice treatment group assignment. Group CompoundFormulation Treatment schedule 1 Vehicle 0.5% Methylcellulose + p.o. QD0.1% Tween-80 2 Compound 258 0.5% Methylcellulose + p.o. QD, 10 mg/kg0.1% Tween-80 3 Compound 258 0.5% Methylcellulose + p.o. QD, 6 mg/kg0.1% Tween-80 4 Compound 258 0.5% Methylcellulose + p.o. QD, 3 mg/kg0.1% Tween-80 5 Compound 258 0.5% Methylcellulose + p.o. QD, 1 mg/kg0.1% Tween-80 6 Compound 279 0.5% Methylcellulose + p.o. QD, 3 mg/kg0.1% Tween-80 7 Compound 253 0.5% Methylcellulose + p.o. QD, 3 mg/kg0.1% Tween-80 8 Compound 284 0.5% Methylcellulose + p.o. QD, 3 mg/kg0.1% Tween-80 p.o. = oral administration (oral gavage). QD = once a day.

TABLE 13 Test compound antitumoral activity on subcutaneous DU-145prostate cancer CDX model in Male BALB/c Nude Mice. Tumor Size (mm³)^(a)T/C Group Treatment Description day 35 (%) P value^(b) 1 Vehicle  693 ±116 — — 2 Compound 258, 47 ± 4 6.8 0.003 10 mg/kg, QD × 4 weeks 3Compound 258, 6 mg/kg, 32 ± 2 4.6 0.002 QD × 4 weeks 4 Compound 258, 3mg/kg, 105 ± 25 15.2 0.003 QD × 4 weeks 5 Compound 258, 1 mg/kg, 378 ±27 54.5 0.4 QD × 4 weeks 6 Compound 279, 3 mg/kg, 516 ± 59 74.5 0.204 QD× 4 weeks 7 Compound 253, 3 mg/kg, 480 ± 49 69.3 0.120 QD × 4 weeks 8Compound 284, 3 mg/kg, 347 ± 48 50.1 0.02 QD × 4 weeks ^(a)Mean ± SEM;^(b)vs. vehicle control (T-test); T/C = tumor-to-control ratio(volume/volume)

Example 324: Cell-Derived Xenograft Mouse Model for Colorectal Cancer

Female BALB/c nude mice (8-9 weeks of age) were injected with HCT116human colon cancer cells. The cells were inoculated subcutaneously intothe left flank of 48 mice. When tumors reached a mean volume ofapproximately 100 mm³, mice were randomly assigned to eight treatmentgroups of each six mice (TABLE 14). Body weights were measured threetimes weekly prior to the initiation of dosing and daily thereafter.Tumor burden was assessed by caliper measurement twice weekly. Dosingbreaks were applied when tolerability issues arose (body weightloss >10%). The study was terminated four weeks post first dosing.Results of the experiment are shown in TABLE 15, FIG. 7 and FIG. 8. Theexperiment was performed in the Crown Bioscience Ltd. (Bejing) testingfacility (Ground Floor, Light Muller Building, Changping Sector ofZhongguancun Scientific Park, No. 21 Huoju Road, Changping District,Bejing, CHN).

TABLE 14 HCT116 CDX mice treatment group assignment. Group CompoundFormulation Treatment schedule 1 Vehicle 0.5% Methylcellulose + p.o. QD0.1% Tween-80 2 Avastin PBS i.v. BIW, 10 mg/kg 3 Compound 258 0.5%Methylcellulose + p.o. BIW, 20 mg/kg 0.1% Tween-80 4 Compound 258 0.5%Methylcellulose + p.o. QD, 6 mg/kg 0.1% Tween-80 5 Compound 258 0.5%Methylcellulose + p.o. QD, 3 mg/kg 0.1% Tween-80 6 Compound 279 0.5%Methylcellulose + p.o. QD, 6 mg/kg 0.1% Tween-80 7 Compound 284 0.5%Methylcellulose + p.o. QD, 6 mg/kg 0.1% Tween-80 8 Compound 284 0.5%Methylcellulose + p.o. QD, 3 mg/kg 0.1% Tween-80 p.o. = oraladministration (oral gavage). i.v. = intravenous administration. QD =once a day. BIW = twice a week.

TABLE 15 Test compound antitumoral activity on subcutaneous HCT116colorectal cancer CDX model in female BALB/c nude mice. Tumor Size(mm³)^(a) T/C Group Treatment Description day 37 (%) P value^(b) 1Vehicle 1187.9 ± 154.3 — — 2 Avastin, 10 mg/kg, BIW 719.9 ± 93.9 60.60.027 3 Compound 258, 696.8 ± 93.7 58.7 0.022 20 mg/kg, BIW 4 Compound258, 253.2 ± 39.2 21.3 <0.001 6 mg/kg, QD 5 Compound 258, 436.2 ± 58.936.7 0.001 3 mg/kg, QD 6 Compound 279, 1064.0 ± 141.1 89.6 0.567 6mg/kg, QD 7 Compound 284,  942.0 ± 114.9 79.3 0.230 6 mg/kg, QD 8Compound 284,  827.4 ± 125.7 69.7 0.100 3 mg/kg, QD ^(a)Mean ± SEM;^(b)vs. vehicle control (T-test); T/C = tumor-to-control ratio(volume/volume) Group-2 vs. Group-3, p = 0.865; Group-2 vs. Group-4, p =0.001; Group-2 vs. Group-5, p = 0.028; Group-2 vs. Group-6, p = 0.070;Group-2 vs. Group-7, p = 0.165; Group-2 vs. Group-8, p = 0.509;

Example 325: Cell-Derived Xenograft Mouse Model for Gastric Cancer

Female BALB/c nude mice (8-9 weeks of age) were injected with MKN45human gastric adenocarcinoma cells. The cells were inoculatedsubcutaneously into the left flank of 48 mice. When tumors reached amean volume of approximately 103 mm³, mice were randomly assigned toeight treatment groups of each six mice (TABLE 16). Body weights weremeasured three times weekly prior to the initiation of dosing and dailythereafter. Tumor burden was assessed by caliper measurement twiceweekly. Dosing breaks were applied when tolerability issues arose (bodyweight loss >10%). The study was terminated four weeks post firstdosing. Results of the experiment are shown in TABLE 17, FIG. 9 and FIG.10. The experiment was performed in the Crown Bioscience Ltd. (Bejing)testing facility (Ground Floor, Light Muller Building, Changping Sectorof Zhongguancun Scientific Park, No. 21 Huoju Road, Changping District,Bejing, CHN).

TABLE 16 MKN45 CDX mice treatment group assignment. Group CompoundFormulation Treatment schedule 1 Vehicle 0.5% Methylcellulose + p.o. QD0.1% Tween-80 2 Paclitaxel PBS i.v. QW, 12 mg/kg 3 Compound 258 0.5%Methylcellulose + p.o. BIW, 20 mg/kg 0.1% Tween-80 4 Compound 258 0.5%Methylcellulose + p.o. QD, 6 mg/kg 0.1% Tween-80 5 Compound 258 0.5%Methylcellulose + p.o. QD, 3 mg/kg 0.1% Tween-80 6 Compound 253 0.5%Methylcellulose + p.o. QD, 6 mg/kg 0.1% Tween-80 7 Compound 284 0.5%Methylcellulose + p.o. QD, 6 mg/kg 0.1% Tween-80 8 Compound 284 0.5%Methylcellulose + p.o. QD, 3 mg/kg 0.1% Tween-80 p.o. = oraladministration (oral gavage). i.v. = intravenous administration. QD =once a day. QW = once a week.

TABLE 17 Test compound antitumoral activity on subcutaneous MKN45gastric cancer CDX model in female BALB/c nude mice. Tumor Size(mm³)^(a) T/C Group Treatment Description day 29 (%) P value^(b) 1Vehicle 1189.6 ± 139.6 — — 2 Paclitaxel, 12 mg/kg, 554.9 ± 52.8 46.60.002 QW 3 Compound 258, 763.4 ± 84.5 64.2 0.026 20 mg/kg, BIW 4Compound 258, 186.9 ± 17.3 15.7 <0.001 6 mg/kg, QD 5 Compound 258, 428.0± 52.5 36.0 <0.001 3 mg/kg, QD 6 Compound 253, 506.5 ± 71.0 42.6 0.001 6mg/kg, QD 7 Compound 284,  592.6 ± 109.7 49.8 0.007 6 mg/kg, QD 8Compound 284, 709.0 ± 55.6 59.6 0.010 3 mg/kg, QD ^(a)Mean ± SEM;^(b)vs. vehicle control (T-test); T/C = tumor-to-control ratio(volume/volume) Group-2 vs. Group-3, p = 0.063; Group-2 vs. Group-4, p <0.001; Group-2 vs. Group-5, p = 0.119; Group-2 vs. Group-6, p = 0.596;Group-2 vs. Group-7, p = 0.764; Group-2 vs. Group-8, p = 0.072

Example 326: Cell-Derived Xenograft Mouse Model for Cervical Cancer

Female BALB/c nude mice (7-9 weeks of age) were injected with SiHa humanHPV16-positive (Human Papillomavirus type 16) cervical cancer cells. Thecells were inoculated subcutaneously into the left flank of 48 mice.When tumors reached a mean volume of approximately 111 mm³, mice wererandomly assigned to eight treatment groups of each six mice (TABLE 18).Body weights were measured three times weekly prior to the initiation ofdosing and daily thereafter. Tumor burden was assessed by calipermeasurement twice weekly. Dosing breaks were applied when tolerabilityissues arose (body weight loss >10%). The study was terminated fourweeks post first dosing. Results of the experiment are shown in TABLE19, FIG. 11 and FIG. 12. The experiment was performed in the CrownBioscience Ltd. (Bejing) testing facility (Ground Floor, Light MullerBuilding, Changping Sector of Zhongguancun Scientific Park, No. 21 HuojuRoad, Changping District, Bejing, CHN).

TABLE 18 SiHa CDX mice treatment group assignment. Group CompoundFormulation Treatment schedule 1 Vehicle 0.5% Methylcellulose + p.o. BID0.1% Tween-80 2 Compound 248 0.5% Methylcellulose + p.o. BID, 1 mg/kg0.1% Tween-80 3 Compound 248 0.5% Methylcellulose + p.o. BID, 3 mg/kg0.1% Tween-80 4 Compound 248 0.5% Methylcellulose + p.o. QD, 6 mg/kg0.1% Tween-80 5 Compound 258 0.5% Methylcellulose + p.o. BID, 1 mg/kg0.1% Tween-80 6 Compound 258 0.5% Methylcellulose + p.o. BID, 3 mg/kg,0.1% Tween-80 p.o. QD from treatment day 7 on 7 Compound 273 0.5%Methylcellulose + p.o. BID, 3 mg/kg 0.1% Tween-80 8 Compound 318 0.5%Methylcellulose + p.o. BID, 3 mg/kg 0.1% Tween-80 p.o. = oraladministration (oral gavage). QD = once a day. BID = twice a day.

TABLE 19 Test compound antitumoral activity on subcutaneousHPV16-positive SiHa cervical cancer CDX model in female BALB/c nudemice. Tumor Size T/C Group Treatment Description (mm³)^(a) day 37 (%) Pvalue^(b) 1 Vehicle 936 ± 89 — — 2 Compound 248, 1 mg/kg, BID 586 ± 8262.6 0.016 3 Compound 248, 3 mg/kg, BID 178 ± 27 19 <0.001 4 Compound248, 6 mg/kg, QD 238 ± 37 25.4 <0.001 5 Compound 258, 1 mg/kg, BID 296 ±27 31.6 <0.001 6 Compound 258, 3 mg/kg, 104 ± 30 11.1 <0.001 BID/QD 7Compound 273, 3 mg/kg, BID  942.0 ± 114.9 79.3 0.230 8 Compound 318, 3mg/kg, BID 351 ± 68 37.5 <0.001 ^(a)Mean ± SEM; ^(b)vs. vehicle control(T-test); T/C = tumor-to-control ratio (volume/volume)

Example 327: Cell-Derived Xenograft Mouse Model for Acute MyeloidLeukemia Tumor Spread (Bone Marrow Engraftment)

Twenty-four female NOD-SCID mice (NOD.CB17-Prkdc^(scid)/J, 4-5 weeks ofage) were pretreated for two days once daily i.p. with 100 mg/kgcyclophosphamide in order to reduce the endogenous bone marrowpopulation and to facilitate bone marrow engraftment of MOLM13-Luccells, an acute myeloid leukemia cell line transduced using a plasmidencoding a luciferase-neomycin fusion protein (cell line identifier#200, Proqinase GmbH, Freiburg, Germany). Forty-eight hours after thelast cyclophosphamide treatment, one million MOLM13-Luc cells in 100 μl0.9% NaCl were intravenously implanted into the animals. In thefollowing study period, the growth of the MOLM13-Luc cells was monitoredon days 4, 8, 11, 15 and 19 using in vivo bioluminescence imaging. Onday 8, animals were randomly assigned to three treatment groups of sixmice each (TABLE 20) and treatment was initiated for all groups on thesame day. The study was terminated 19 days post first dosing. Animalswere weighed and euthanized by cervical dislocation. Selected organs(femur, lumbar spine, lymph nodes (inguinal and axillary) and peritonealcarcinomatosis samples from fatty tissues) were collected, weighed,appropriately processed and the luciferase activity of the homogenatesmeasured using an ex vivo luciferase assay (#E1501, Promega, Madison,Wis., USA) according to the instructions from the manufacturer. Theluciferase activity was read with an Enspire Reader (Perkin Elmer,Waltham, Mass., USA). Except for lymph nodes, organ weights weredetermined during necropsy in order to normalize luciferase activities.Results of the experiment are shown in FIGS. 13-15. The experiment wasperformed in the Proqinase animal test facility (Proqinase GmbH, D-79106Freiburg, Germany).

TABLE 20 MOLM13-Luc CDX mice treatment group assignment. Group CompoundFormulation Treatment schedule 1 Vehicle 0.5% Methylcellulose + p.o. QD0.1% Tween-80 2 Compound 258 0.5% Methylcellulose + p.o. QD, 1 mg/kg0.1% Tween-80 3 Compound 258 0.5% Methylcellulose + p.o. QD, 3 mg/kg0.1% Tween-80 4 Compound 258 0.5% Methylcellulose + p.o. QD, 6 mg/kg0.1% Tween-80 p.o. = oral administration (oral gavage). QD = once a day.

Example 328: Patient-Derived Xenograft Mouse Model for Head-and-NeckSquamous Cell Carcinoma

Female NMRI nu/nu mice were injected with cells derived from a humanhead-and-neck cancer (model #HN10309, an HPV-positive head-and-necksquamous cell carcinoma, EPO-GmbH, Berlin, Germany). The cells wereinoculated subcutaneously into the left flank of 24 mice. Thirty-threedays later tumors reached a mean volume of approximately 116 mm³, andmice were randomly assigned to three treatment groups of each eight mice(TABLE 21). Body weights were measured twice weekly. Tumor burden wasassessed by caliper measurement twice weekly. Dosing breaks were appliedwhen tolerability issues arose (body weight loss >10%). The study wasterminated four weeks post first dosing. Results of the experiment areshown in TABLE 22, FIG. 16 and FIG. 17. The experiment was performed inthe EPO animal testing facility (Experimental Pharmacology and OncologyGmbH, 13125 Berlin-Buch, Germany).

TABLE 21 HNSCC PDX mice treatment group assignment. Group CompoundFormulation Treatment schedule A Vehicle 0.5% Methylcellulose + p.o. BID0.1% Tween-80 B Compound 282 0.5% Methylcellulose + p.o. BID, 30 mg/kg0.1% Tween-80 C Compound 248 0.5% Methylcellulose + p.o. BID, 30 mg/kg0.1% Tween-80 p.o. = oral administration (oral gavage). BID = twice aday.

TABLE 22 Test compound antitumoral activity on subcutaneous HPV-positiveHNSCC model in female NMRI nu/nu mice. Bonferroni posttests to vehiclegroup (mean TV values in cm³). Compound Compound Day Vehicle 282Significance 248 Significance 33 0.1156 0.1161 ns 0.1159 ns 35 0.14990.1308 ns 0.1248 ns 38 0.2386 0.1751 ns 0.1389 ns 41 0.2908 0.2086 ns0.1093 * 45 0.3670 0.3560 ns 0.1794 * 49 0.5079 0.4920 ns 0.2398 *** 530.6693 0.6364 ns 0.2964 *** 56 0.6875 0.6558 ns 0.2569 *** ns notsignificant * = p < 0.05, ** = p < 0.01; *** = p < 0.001.

Example 329: Patient-Derived Xenograft Mouse Model for Head-and-NeckSquamous Cell Carcinoma

Female NMRI nu/nu mice were injected with cells derived from a humanhead-and-neck cancer (model #HN11303, an HPV-positive head-and-necksquamous cell carcinoma, EPO-GmbH, Berlin, Germany). The cells wereinoculated subcutaneously into the left flank of 40 mice. Thirteen dayslater tumors reached a mean volume of approximately 107 mm³, and micewere randomly assigned to five treatment groups of each eight mice(TABLE 23). Body weights were measured twice weekly. Tumor burden wasassessed by caliper measurement twice weekly. Dosing breaks were appliedwhen tolerability issues arose (body weight loss >10%). The study wasterminated five weeks post first dosing. Results of the experiment areshown in TABLE 24, FIG. 18 and FIG. 19. The experiment was performed inthe EPO animal testing facility (Experimental Pharmacology and OncologyGmbH, 13125 Berlin-Buch, Germany).

TABLE 23 HNSCC PDX mice treatment group assignment. Group CompoundFormulation Treatment schedule A Vehicle 0.5% Methylcellulose + 0.1%i.p. BID Tween-80 B Compound 57 0.5% Methylcellulose + i.p. BID, 30mg/kg 0.1% Tween-80 C Compound 248 0.5% Methylcellulose + i.p. BID, 30mg/kg day 13-17 0.1% Tween-80 dosing break day 18-19 i.p. QD, 10 mg/kgday 20 i.p. QD, 3 mg/kg day 21-31 i.p. QD, 10 mg/kg day 32-47 D Compound282 0.5% Methylcellulose + i.p. BID, 30 mg/kg 0.1% Tween-80 E Compound273 0.5% Methylcellulose + i.p. BID, 30 mg/kg day 13-27 0.1% Tween-80dosing break day 28-31 i.p. QD, 10 mg/kg day 32-47 i.p. =intraperitoneal injection. BID = twice a day. QD = once a day.

TABLE 24 Test compound antitumoral activity on subcutaneous HPV-positiveHNSCC model in female NMRI nu/nu mice. Compound Compound CompoundCompound Day Vehicle 57 Sign. 248 Sign. 282 Sign. 273 Sign. 13 0.10600.1073 ns 0.1064 ns 0.1073 ns 0.1063 ns 15 0.1286 0.1106 ns 0.0958 ns0.1061 ns 0.1073 ns 18 0.1363 0.1166 ns 0.0916 ns 0.1040 ns 0.0948 ns 210.1566 0.1081 ns 0.0511 *** 0.0971 * 0.0875 ** 25 0.1650 0.1233 ns0.0499 *** 0.1111 ns 0.0451 *** 29 0.1805 0.1421 ns 0.0288 *** 0.1030*** 0.0194 *** 33 0.2081 0.2009 ns 0.0068 *** 0.1273 *** 0.0056 *** 360.1988 0.1776 ns 0.0041 *** 0.1185 *** 0.0031 *** Bonferroni postteststo vehicle group (mean TV values in cm³). ns not significant; * = p <0.05; ** = p < 0.01; *** = p < 0.001. According to RECIST guidelines(Response Evaluation Criteria In Solid Tumors; Eisenhauer et al., Eur.J. Cancer 45 (2009) 228-247), treatment outcome of all mice in group C(Compound 248) and E (Compound 273) was classified as completeremission.

Example 330: Cell-Derived Syngeneic Mouse Model for Colorectal CarcinomaCombined with an Immuno-Oncology Treatment

Female BALB/c mice (6-8 weeks of age) were injected with cells derivedfrom a syngeneic chemically induced colon cancer (CT-26 cells). Thecells were inoculated subcutaneously into the left flank of 60 mice.After seven days, tumors reached a mean volume of approximately 100 mm³,and mice were randomly assigned to six treatment groups of each ten mice(TABLE 25). Body weights were measured daily until treatment start, thentwice weekly. Tumor burden was assessed twice weekly by calipermeasurement. The study was terminated four weeks post first dosing.Results of the experiment are shown in TABLE 26, FIG. 20 and FIG. 21.The experiment was performed in the Crown Bioscience Inc. (Beijing)animal testing facility (Ground Floor, Light Muller Building, ChangpingSector of Zhongguancun Scientific Park, No. 21 Huoju Street, ChangpingDistrict, Beijing, China, 102200).

TABLE 25 CT26 tumor model mice treatment group assignment. TreatmentGroup Compound Formulation schedule 1 Vehicle 0.5% Methylcellulose +p.o. QD, Vehicle 0.1% Tween-80 i.p BIW 2 Vehicle 0.5% Methylcellulose +p.o. QD, Anti-PD-1* 0.1% Tween-80 i.p BIW, 10 mg/kg 3 Compound 258 0.5%Methylcellulose + p.o. QD, 1 mg/kg Vehicle 0.1% Tween-80 i.p BIW 4Compound 258 0.5% Methylcellulose + p.o. QD, 3 mg/kg Vehicle 0.1%Tween-80 i.p BIW 5 Compound 258 0.5% Methylcellulose + p.o. QD, 1 mg/kgAnti-PD-1* 0.1% Tween-80 i.p BIW, 10 mg/kg 6 Compound 258 0.5%Methylcellulose + p.o. QD, 3 mg/kg Anti-PD-1* 0.1% Tween-80 i.p BIW, 10mg/kg p.o. = oral administration (oral gavage). BIW = twice a week. QD =once a day. *= RMP1-14 antibody.

TABLE 26 Survival data for test compound antitumoral activity onsubcutaneous syngeneic colon cancer model in female BALB/c mice incombination with anti-PD1 antibodies Compound Compound Compound Compound258 258 Anti- 258 258 1 mg/kg + 3 mg/kg + Day Vehicle PD1 1 mg/kg 3mg/kg Anti-PD1 Anti-PD1 21 10 10 10 10 10  10  23 9 10 10 8 10  10  25 77 5 6 10  10  28 2 5 2 2 7 9 30 1 5 1 0 6 8 32 0 3 0 0 4 4 34 0 3 0 0 44 36 0 3 0 0   4(*)   4(*) (mice alive between day 21 and day 36 of theexperiment). (*)One mouse in group 5 (combination of Compound 258 1mg/kg and anti-PD1 antibodies) and one mouse in group 6 (combinationCompound 258 3 mg/kg and anti-PD1 antibodies) had a complete tumorregression (tumor volume not measurable).

Example 331: P300/CBP—Androgen Receptor Target Gene ExpressionRegulation in Prostate Cancer Cells

LNCaP prostate cancer cells (CLS GmbH) were seeded at a density of15′000 cells/cm² in 48-well cell culture-treated plates and cultured for72 hours in RPMI1640 medium (Sigma-Aldrich) supplemented with Glutamax I(ThermoFisher-Gibco), “Antibiotic and Antimycotic Solution”(Sigma-Aldrich) and 1% fetal calf serum (Sigma-Aldrich). AR-driven geneexpression response was induced by addition of the androgen signalingagonist dihydrotestosterone (Selleck Chemicals, Houston, Tex., USA) to aconcentration of 100 nanomol/Lt for 4 hours. Cells were treated withCompound 258 during dihydrotestosterone induction. Culture medium wascarefully removed, cells were washed 1× with Phosphate-Buffered Saline(Sigma-Aldrich) and lysed using the SingleShot Cell Lysis Kit (Bio-Rad,Hercules, Calif., USA). Gene expression of well-known AR-responsivegenes prostate-specific antigen (KLK3, ThermoFisher), transmembraneserine protease 2 (TMPRSS2, ThermoFisher) and prostein (SLC45A3,ThermoFisher) was assessed by quantitative PCR after reversetranscription of the LNCaP RNA with the Applied Biosystem High-CapacitycDNA Reverse Transcription Kit (ThermoFisher). Gene expression wasnormalized against four reference genes (RPLPO, GUSB, GAPDH and ACTB,all probe detection systems were from Bio-Rad). Results of theexperiment are shown in FIG. 22.

Example 332: P300/CBP—Androgen Receptor-Dependent Protein ExpressionRegulation in a Castration-Resistant Prostate Cancer Patient-DerivedXenograft Mouse Model

Mice from groups 1, 3 and 4 of the CPRC prostate patient-derivedxenograft model (TABLE 9, EXAMPLE 322) were used to analyze serum PSA atthe end of the experiment. In groups 3 and 4, only serum from mice thathad a detectable tumor was analyzed. PSA was detected by ELISA (HumanKallikrein 3/PSA Quantikine ELISA Kit, R&D Systems, Minneapolis, Minn.,USA) according to manufacturer's instructions. Minimal relative expectedPSA-levels were calculated based on minimal PSA/tumor size ratio ofvehicle-treated mice. Results of the analysis are presented in FIG. 22.

Example 333: P300/CBP—Hypoxia Inducible Factor Alpha-Dependent ProteinExpression Regulation in Two Gastric/Colorectal Cancer Cell-DerivedXenograft Mouse Model

Mice from groups 1, 2, 4 and 5 of the HCT-116 colorectal cancer model(TABLE 12, EXAMPLE 324) and MKN45 gastric cancer model (TABLE 14,EXAMPLE 325) were used to analyze tumor Vascular Endothelial GrowthFactor A (VEGF) protein expression at the end of the experiment. Tumorshomogenates were prepared using a 2× Lysis Buffer (RayBiotech Life,Norcross, Ga., USA) according to manufacturer's instructions. VEGF wasquantified in 50 micrograms tumor by ELISA (Human VEGF Quantikine ELISAKit, R&D Systems) according to manufacturer's instructions. Results ofthe analysis are presented in FIG. 24.

Example 334: P53 Protein Reactivation in an HPV16-Positive CervicalCancer Tumor Cell Line

HPV16-positive cervical cancer cells CaSki were subcultured as describedin EXAMPLE 1, seeded at a density of 20′000 cells/cm²; and readilytreated with Compound 258 for 72 hrs. For western blot analysis, cellswere removed from the cell culture vessels by trypsinization, washedtwice with PBS (Sigma-Aldrich), lysed with a RIPA-buffer/Proteaseinhibitor cocktail (Sigma-Aldrich) by shaking on ice for 30 minutesfollowed by sonication on ice, 20 minutes centrifugation at 16′000×g, 4°C. Lysates were mixed 1:1 with 4× Lämmli Buffer (Bio-Rad) prior toloading onto a Mini-PROTEAN TGX precast 4-20% PAGE gel (Bio-Rad). Gelswere run for 1 hour at 110V. Gel were transferred to a Trans-Blot TurboMini PVDF membrane (Bio-Rad) using a Bio-Rad Trans-Blot Turbo Systemaccording to manufacturer's instructions. Equal amounts of cells wereused, and the total transferred protein visualized on a Bio-Rad ChemiDocTouch Imager prior to incubation with the primary antibody. Afterblocking for 1 hr with 5% non-fat-dry-milk (for p53 detection) or 5% BSA(for detection of p53-acetyllysine-382) in 1×TBS with 0.1% Tween-20(Bio-Rad), blots were incubated overnight at 4° C. with p53 orp53-acetyl-lysine-382-specific antibodies (mouse monoclonal antibodies(SC-47698 from Santa Cruz Biotechnologies, Dallas, Tex., USA),respectively rabbit polyclonal antibodies (#2525S from Cell SignalingTechnologies, Boston, Mass., USA), both at 1:1′000 dilution) andsubsequently with the corresponding secondary HRP-conjugated antibodies(Cell Signaling Technologies, both 1:1′000 dilution) according tomanufacturer's instructions. Specific antibody binding was detected withthe SuperSignal West Femto Maximum Sensitivity Substrate (ThermoFisher)and visualized using a Bio-Rad ChemiDoc Touch Imager. Results from theexperiment are shown in FIG. 25.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments and methods described herein. Such equivalents are intendedto be encompassed by the scope of the present application.

All patents, patent applications, and literature references cited hereinare hereby expressly incorporated by reference.

1. A compound of formula (Ia)

or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein: R¹ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substitutedby cycloalkyl, aryl or heteroaryl, wherein the cycloalkyl, aryl or theheteroaryl is optionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅cycloalkyl; R² is selected from H, C(O)R¹⁴, C(O)NR¹⁵R¹⁵, C(O)OR¹⁵, C₁₋₇alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl,C₁₋₅ alkyl-OR⁸, C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl,C₁₋₅ alkyl-NHCOR¹³, or C₁₋₃ alkyl substituted by cycloalkyl, aryl orheteroaryl, wherein the cycloalkyl, aryl or the heteroaryl is optionallysubstituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; with the provisothat when R² is C(O)NR¹⁵R¹⁵, both R¹⁵ can form a ring wherein the ringcontains the N of NR¹⁵R¹⁵ and optionally one further heteroatom selectedfrom O and N, wherein if the one further heteroatom is N, it isoptionally substituted by R⁸; R³ and R⁷ are each independently selectedfrom H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇cycloalkenyl, all optionally substituted by halogen, OR⁸, NR⁸R¹¹, orC₁₋₃ alkyl substituted by aryl or heteroaryl, wherein the aryl or theheteroaryl is optionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅cycloalkyl; R⁴ is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl,C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted bycycloalkyl, aryl or heteroaryl, wherein the cycloalkyl, aryl or theheteroaryl is optionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅cycloalkyl; R⁵ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, C₁₋₃ alkyl-OR⁸, orSR⁸; and wherein R⁵ can form a ring with any part of X or Y, wherein thering optionally contains a carbonyl group; R⁶ is selected from H, C₁₋₇alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloakenyl,all optionally substituted by halogen, OR⁸, NR⁸R¹¹; C₁₋₃ alkylsubstituted by C(O)NR⁸R¹¹; or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; and wherein R⁶ can form aring with any part of X; or is imidazolidinone; R⁸ and R¹¹ are eachindependently selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl,C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl; X is selected from a bond, C₁₋₇alkanediyl, C₂₋₇ alkenediyl, C₂₋₇ alkynediyl, C₃₋₉ cycloalkanediyl, C₄₋₆cycloalkenediyl, —O—, C₁₋₃ alkanediyl-O—, —O—C₁₋₇ alkanediyl, —O—C₃₋₉cycloalkanediyl, C₁₋₃ alkanediyl-O—C₁₋₇ alkanediyl, C₁₋₇heteroalkanediyl, or —S—C₁₋₇ alkanediyl; and wherein X can form a ringor a polycyclic system with any part of R⁵, R⁶, or Y, wherein the ringoptionally contains a carbonyl group; Y is selected from H, C(O)NR¹⁰R¹²,C(O)OR¹⁰, R¹¹NC(O)NR¹⁰R¹², OC(O)R¹⁰, OC(O)NR¹⁰R¹², S(O)_(n)R⁸ wherein nis 0, 1 or 2, SO₂NR¹⁰R¹², NR¹⁰SO₂R¹⁰, NR¹⁰R¹², HNCOR⁸, CN,C₃₋₇-cycloalkyl optionally containing a heteroatom in the ring selectedfrom O and N wherein if the heteroatom is N it is optionally substitutedby R⁸; S-aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl,O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one ormore R⁹ or R¹⁴; or aryl, heteroaryl wherein the aryl or heteroaryl isoptionally substituted by one or more of R⁸; and wherein Y can form aring with any part of X or R⁵, wherein the ring optionally contains acarbonyl group; with the proviso that when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹²,R¹⁰ and R¹² can form a ring wherein the ring contains the N of NR¹⁰R¹²and optionally one further heteroatom selected from O and N, wherein ifthe one further heteroatom is N, it is optionally substituted by R⁸; R⁹is selected from H, halogen, C₁₋₅ alkyl, C₂₋₅ alkenyl, C₂₋₅ alkynyl,C₃₋₅ cycloalkyl, C₁₋₅ alkyl-OR⁸, C₁₋₅ alkyl-SR⁸, C₁₋₅ alkyl-NR⁸R¹¹, C₁₋₅alkyl-C(O)OR⁸, C₁₋₅ alkyl-C(O)NR⁸R¹¹, C₁₋₅ alkyl-C(O)R¹⁰, CN, C(O)R⁸,C(O)NR⁸R¹¹, C(O)OR⁸, NR⁸C(O)NR⁸R¹¹, OC(O)NR⁸R¹¹, SO₂NR⁸R¹¹, NR⁸SO₂R⁸,OR⁸, NR⁸R¹¹, or S(O)_(n)R⁸ wherein n is 0, 1 or 2; R¹⁰ and R¹² are eachindependently selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl,C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₃ alkanediyl-O—C₁₋₃alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₃ alkyl-aryl, or C₁₋₃ alkyl-heteroaryl,all these groups optionally substituted by halogen, OR⁸, or NR⁸R¹¹; R¹³is C₁₋₅ alkyl substituted by a bicyclic ring optionally containing atleast one heteroatom and a carbonyl group; R¹⁴ is selected from H, C₁₋₇alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl,or C₁₋₃ alkyl substituted by aryl or heteroaryl, wherein the aryl or theheteroaryl is optionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅cycloalkyl; and each R¹⁵ is independently selected from H, C₁₋₇ alkyl,C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, orC₁₋₃ alkyl-OR⁸.
 2. A compound of formula (I)

or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein: R¹ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substitutedby aryl or heteroaryl, wherein the aryl or the heteroaryl is optionallysubstituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; R² is selectedfrom H, C(O)R¹⁴, C(O)NR¹⁵R¹⁵, C(O)OR¹⁵, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₅ alkyl-OR⁸, C₁₋₃alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₅ alkyl-NHCOR¹³, orC₁₋₃ alkyl substituted by aryl or heteroaryl, wherein the aryl or theheteroaryl is optionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅cycloalkyl; with the proviso that when R² is C(O)NR¹⁵R¹⁵, both R¹⁵ canform a ring wherein the ring contains the N of NR¹⁵R¹⁵ and optionallyone further heteroatom selected from O and N, wherein if the one furtherheteroatom is N, it is optionally substituted by R⁸; R³ and R⁷ are eachindependently selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl,C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, all optionally substituted byhalogen, OR⁸, NR⁸R¹¹; or C₁₋₃ alkyl substituted by aryl or heteroaryl,wherein the aryl or the heteroaryl is optionally substituted by halogen,C₁₋₄ alkyl or C₃₋₅ cycloalkyl; R⁴ is selected from C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkylsubstituted by aryl or heteroaryl, wherein the aryl or the heteroaryl isoptionally substituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; R⁵ isselected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, C₁₋₃ alkyl-OR⁸, or SR⁸; and whereinR⁵ can form a ring with any part of X or Y, wherein the ring optionallycontains a carbonyl group; R⁶ is selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, alloptionally substituted by halogen, OR⁸, NR⁸R¹¹; or C₁₋₃ alkylsubstituted by C(O)NR⁸R¹¹; C₁₋₃ alkyl substituted by aryl or heteroaryl,wherein the aryl or the heteroaryl is optionally substituted by halogen,C₁₋₄ alkyl or C₃₋₅ cycloalkyl; or is imidazolidinone; R⁸ and R¹¹ areeach independently selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl; X is selected from abond, C₁₋₇ alkanediyl, C₂₋₇ alkenediyl, C₂₋₇ alkynediyl, C₃₋₆cycloalkanediyl, C₄₋₆ cycloalkenediyl, —O—, C₁₋₃ alkanediyl-O—, —O—C₁₋₇alkanediyl, C₁₋₃ alkanediyl-O—C₁₋₇ alkanediyl, C₁₋₇ heteroalkanediyl, or—S—C₁₋₇ alkanediyl; and wherein X can form a ring with any part of R⁵ orY, wherein the ring optionally contains a carbonyl group; Y is selectedfrom H, C(O)NR¹⁰R¹², C(O)OR¹⁰, R¹¹NC(O)NR¹¹R¹², OC(O)R¹⁰, OC(O)NR¹⁰R¹²,S(O)_(n)R⁸ wherein n is 0, 1 or 2, SO₂NR¹⁰R¹², NR¹⁰SO₂R¹⁰, NR¹⁰R¹²,HNCOR⁸, CN, C₃₋₇-cycloalkyl optionally containing a heteroatom in thering selected from O and N wherein if the heteroatom is N it isoptionally substituted by R⁸; S-aryl, O-aryl, S-heteroaryl, O-heteroarylwherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionallysubstituted by one or more R⁹ or R¹⁴; aryl, or heteroaryl wherein thearyl or heteroaryl is optionally substituted by one or more of R⁸; andwherein Y can form a ring with any part of X or R⁵, wherein the ringoptionally contains a carbonyl group; with the proviso that when Y isC(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² can form a ring wherein the ringcontains the N of NR¹⁰R¹² and optionally one further heteroatom selectedfrom O and N, wherein if the one further heteroatom is N, it isoptionally substituted by R⁸; R⁹ is selected from H, halogen, C₁₋₅alkyl, C₂₋₅ alkenyl, C₂₋₅ alkynyl, C₃₋₅ cycloalkyl, C₁₋₅ alkyl-OR⁸, C₁₋₅alkyl-SR⁸, C₁₋₅ alkyl-NR⁸R¹¹, C₁₋₅ alkyl-C(O)OR⁸, C₁₋₅ alkyl-C(O)NR⁸R¹¹,C₁₋₅ alkyl-C(O)R¹⁰, CN, C(O)R⁸, C(O)NR⁸R¹¹, C(O)OR⁸, NR⁸C(O)NR⁸R¹¹,OC(O)NR⁸R¹¹, SO₂NR⁸R¹¹, NR⁸SO₂R⁸, OR⁸, NR⁸R¹¹, or S(O)_(n)R⁸ wherein nis 0, 1 or 2; R¹⁰ and R¹² are each independently selected from H, C₁₋₇alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl,C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₃ alkyl-aryl, orC₁₋₃ alkyl-heteroaryl, all these groups optionally substituted byhalogen, OR⁸, or NR⁸R¹¹; R¹³ is C₁₋₅ alkyl substituted by a bicyclicring optionally containing at least one heteroatom and a carbonyl group;R¹⁴ is selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl; and each R¹⁵ is independentlyselected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, OR⁸, or C₁₋₃ alkyl-OR⁸.
 3. The compoundaccording to any one of the previous claims, wherein R¹ is selected fromC₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, or C₁₋₃ alkyl substituted by aryl or heteroaryl, whereinthe aryl or the heteroaryl is optionally substituted by halogen, C₁₋₄alkyl or C₃₋₅ cycloalkyl.
 4. The compound according to any one of theprevious claims, wherein R¹ is selected from C₂₋₇ alkyl, C₃₋₇cycloalkyl, or C₁₋₃ alkyl substituted by aryl or heteroaryl, wherein thearyl or the heteroaryl is optionally substituted by halogen, C₁₋₄ alkylor C₃₋₅ cycloalkyl.
 5. The compound according to any one of the previousclaims, wherein R¹ is selected from C₃₋₇ alkyl, C₃₋₇ cycloalkyl, or C₁₋₃alkyl substituted by aryl or heteroaryl.
 6. The compound according toany one of the previous claims, wherein R² is selected from H, C(O)R¹⁴,C(O)OR¹⁵, C₁₋₇ alkyl, C₃₋₇ cycloalkyl, C₁₋₃ alkanediyl-O—C₁₋₃alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₅ alkyl-OR⁸, C₁₋₅ alkyl-NHCOR¹³, orC₁₋₃ alkyl substituted by aryl, wherein the aryl is optionallysubstituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl.
 7. The compoundaccording to any one of the previous claims, wherein R² is selected fromH, C(O)R¹⁴, wherein R¹⁴ is C₁₋₇ alkyl; C₁₋₇ alkyl, C₃₋₇ cycloalkyl, C₁₋₅alkyl-OR⁸, C₁₋₅ alkyl-NHCOR¹³, wherein R¹³ ispentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3-one; orC₁₋₃ alkyl substituted by aryl, wherein the aryl is optionallysubstituted by halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl.
 8. The compoundaccording to any one of the previous claims, wherein R³ and R⁷ are eachindependently selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl,C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl.
 9. The compound according to anyone of the previous claims, wherein R³ and R⁷ are H.
 10. The compoundaccording to any one of the previous claims, wherein R⁴ is selected fromC₁₋₇ alkyl, C₃₋₇ cycloalkyl, or C₁₋₃ alkyl substituted by aryl orheteroaryl, wherein the aryl or the heteroaryl is optionally substitutedby halogen, C₁₋₄ alkyl or C₃₋₅ cycloalkyl.
 11. The compound according toany one of the previous claims, wherein R⁴ is selected from C₂₋₇ alkyl,C₃₋₇ cycloalkyl, or C₁₋₃ alkyl substituted by aryl or heteroaryl,wherein the aryl or the heteroaryl is optionally substituted by halogen,C₁₋₄ alkyl or C₃₋₅ cycloalkyl.
 12. The compound according to any one ofthe previous claims, wherein R⁴ is selected from C₃₋₇ alkyl, C₃₋₇cycloalkyl, or C₁₋₃ alkyl substituted by aryl or heteroaryl.
 13. Thecompound according to any one of the previous claims, wherein thecompound is of any one of Formulae (IIa), (IIb), or (IIc):

or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X, and Y are as describedherein.
 14. The compound according to any one of the previous claims,wherein the compound is of any one of Formulae (IIIa), (IIIb), (IIIc),or (IIId):

or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein R¹, R⁴, R⁵, R⁶, X, and Y are as described herein. 15.The compound according to any one of the previous claims, wherein R⁵ isselected from H, C₁₋₇ alkyl, OR⁸, or SR⁸; and wherein C₁₋₇ alkyl, OR⁸ orSR⁸ of R⁵ can form a ring with any part of X or Y, wherein the ringoptionally contains a carbonyl group.
 16. The compound according to anyone of the previous claims, wherein R⁶ is selected from H, C₁₋₇ alkyl,C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₃₋₇ cycloalkyl, or C₄₋₇ cycloalkenyl; or isimidazolidinone.
 17. The compound according to any one of the previousclaims, wherein R⁶ is H, C₁₋₇ alkyl, or imidazolidinone.
 18. Thecompound according to any one of the previous claims, wherein thecompound is of any one of Formulae (IVa), (IVb), (IVc) or (IVd):

or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein R¹, R², R⁴, R⁵, R⁶, X, and Y are as described herein.19. The compound according to any one of the previous claims, wherein R⁸and R¹¹ are each independently selected from H, C₁₋₇ alkyl, C₂₋₇alkenyl, or C₃₋₇ cycloalkyl.
 20. The compound according to any one ofthe previous claims, wherein R⁹ is selected from H, C₁₋₅ alkyl, halogen,C₁₋₅ alkyl-NR⁸R¹¹, C₁₋₅ alkyl-C(O)OR⁸, C₁₋₅ alkyl-C(O)NR⁸R¹¹, CN,C(O)R⁸, C(O)NR⁸R¹¹, C(O)OR⁸, or OR⁸.
 21. The compound according to anyone of the previous claims, wherein R¹⁰ and R¹² are each independentlyselected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₃alkyl-aryl, or C₁₋₃ alkyl-heteroaryl, all these groups optionallysubstituted by halogen or OR⁸.
 22. The compound according to any one ofthe previous claims, wherein R¹⁴ is selected from C₁₋₇ alkyl, C₃₋₇cycloalkyl, or C₁₋₃ alkyl substituted by aryl or heteroaryl, wherein thearyl or the heteroaryl is optionally substituted by halogen, C₁₋₄ alkylor C₃₋₅ cycloalkyl.
 23. The compound according to any one of theprevious claims, wherein R¹⁴ is selected from C₁₋₇ alkyl or C₃₋₇cycloalkyl.
 24. The compound according to any one of the previousclaims, wherein R¹⁴ is C₁₋₇ alkyl.
 25. The compound according to any oneof the previous claims, wherein each R¹⁵ is independently selected fromH, C₁₋₇ alkyl, or C₃₋₇ cycloalkyl.
 26. The compound according to any oneof the previous claims, wherein each R¹⁵ is independently selected fromH, C₁₋₇ alkyl.
 27. The compound according to any one of the previousclaims, wherein X is selected from a bond, C₁₋₇ alkanediyl, —O—, C₁₋₃alkanediyl-O—, —O—C₁₋₇ alkanediyl, C₁₋₃ alkanediyl-O—C₁₋₇ alkanediyl,C₁₋₇ heteroalkanediyl, or —S—C₁₋₇ alkanediyl; and wherein X can form aring with any part of R⁵ or Y, wherein the ring optionally contains acarbonyl group.
 28. The compound according to any one of the previousclaims, wherein X is selected from a bond and C₁₋₇ alkanediyl, andwherein C₁₋₇ alkanediyl of X can form a ring with any part of Y.
 29. Thecompound according to any one of the previous claims, wherein X isselected from a bond, —O—C₁₋₇ alkanediyl, —S—C₁₋₇ alkanediyl and C₁₋₇alkanediyl, and wherein —O—C₁₋₇ alkanediyl, —S—C₁₋₇ alkanediyl or C₁₋₇alkanediyl of X can form a ring with any part of R⁵, wherein the ringoptionally contains a carbonyl group.
 30. The compound according to anyone of the previous claims, wherein Y is selected from H, C(O)NR¹⁰R¹²,C(O)OR¹⁰, NR¹⁰R¹², CN, C₃₋₇-cycloalkyl optionally containing aheteroatom in the ring selected from O and N wherein if the heteroatomis N it is optionally substituted by R⁸; S-aryl, O-aryl, S-heteroaryl,O-heteroaryl wherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl areoptionally substituted by one or more R⁹ or R¹⁴; or aryl, heteroarylwherein the aryl or heteroaryl is optionally substituted by one or moreof R⁸; and wherein when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², Y can form a ringwith any part of X or R⁵, wherein the ring optionally contains acarbonyl group; with the proviso that when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹²,R¹⁰ and R¹² can form a ring wherein the ring contains the N of NR¹⁰R¹²and optionally one further heteroatom selected from O and N, wherein ifthe one further heteroatom is N, it is optionally substituted by R⁸. 31.The compound according to any one of the previous claims, wherein Y isselected from H, C(O)NR¹⁰R¹², C(O)OR¹⁰, NR¹⁰R¹², CN, C₃₋₇-cycloalkyloptionally containing a heteroatom in the ring selected from O and Nwherein if the heteroatom is N it is optionally substituted by R⁸;S-aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl, O-aryl,S-heteroaryl, O-heteroaryl are optionally substituted by one or more R⁹or R¹⁴; or aryl, heteroaryl wherein the aryl or heteroaryl is optionallysubstituted by one or more of R⁸; and wherein Y can form a ring with anypart of X or R⁵, wherein the ring optionally contains a carbonyl group;with the proviso that when Y is C(O)NR¹⁰R¹² or NR¹⁰R¹², R¹⁰ and R¹² canform a ring wherein the ring contains the N of NR¹⁰R¹² and optionallyone further heteroatom selected from O and N, wherein if the one furtherheteroatom is N, it is optionally substituted by R⁸.
 32. The compoundaccording to any one of the previous claims, wherein Y is selected fromC(O)NR¹⁰R¹², NR¹⁰R¹², C₃₋₇-cycloalkyl optionally containing a heteroatomin the ring selected from O and N wherein if the heteroatom is N it isoptionally substituted by R⁸; S-aryl, O-aryl, S-heteroaryl, O-heteroarylwherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionallysubstituted by one or more R⁹ or R¹⁴; or heteroaryl wherein theheteroaryl is optionally substituted by one or more of R⁸; and wherein Ycan form a ring with any part of X or R⁵, wherein the ring optionallycontains a carbonyl group; with the proviso that when Y is C(O)NR¹⁰R¹²or NR¹⁰R¹², R¹⁰ and R¹² can form a ring wherein the ring contains the Nof NR¹⁰R¹² and optionally one further heteroatom selected from O and N,wherein if the one further heteroatom is N, it is optionally substitutedby R⁸.
 33. The compound according to any one of the previous claims,wherein the compound is of any one of Formulae (Va), (Vb), (Vc), or(Vd):

or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3,and R¹, R², R³, R⁴, R⁶, R⁷, R¹⁰ and R¹² are as described herein.
 34. Thecompound according to any one of the previous claims, wherein thecompound is of any one of Formulae (VIa), (VIb), (VIc), or (VId):

or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3,and R¹, R², R³, R⁴, R⁶, R⁷, R¹⁰ and R¹² are as described herein.
 35. Thecompound according to any one of the previous claims, wherein Y isselected from NR¹⁰R¹² and C₃₋₇-cycloalkyl optionally containing aheteroatom in the ring selected from O and N wherein if the heteroatomis N it is optionally substituted by R⁸; and wherein Y can form a ringwith any part of X or R⁵; with the proviso that when Y is NR¹⁰R¹², R¹⁰and R¹² can form a ring wherein the ring contains the N of NR¹⁰R¹² andoptionally one further heteroatom selected from O and N, wherein if theone further heteroatom is N, it is optionally substituted by R⁸.
 36. Thecompound according to any one of the previous claims, wherein R⁵ isselected from H and C₁₋₇ alkyl; wherein C₁₋₇ alkyl of R⁵ can form a ringwith any part of Y; wherein X is selected from a bond and C₁₋₇alkanediyl, and wherein C₁₋₇ alkanediyl of X can form a ring with anypart of Y; wherein Y is selected from NR¹⁰R¹² and C₃₋₇-cycloalkyloptionally containing a heteroatom in the ring wherein the heteroatom isN and is optionally substituted by R⁸ wherein R⁸ is C₁₋₇ alkyl; whereinY can form a ring with any part of C₁₋₇ alkanediyl of X or with any partof C₁₋₇ alkyl of R⁵; with the proviso that when Y is NR¹⁰R¹², R¹⁰ andR¹² can form a ring wherein the ring contains the N of NR¹⁰R¹² andoptionally one further heteroatom selected from O and N, wherein if theone further heteroatom is N, it is optionally substituted by R⁸; andwherein R¹⁰ and R¹² are each independently selected from H, C₁₋₇ alkyl,C₃₋₇ cycloalkyl, C₁₋₃ alkyl-aryl, all these groups optionallysubstituted by halogen.
 37. The compound according to any one of theprevious claims, wherein R⁵ is selected from C₁₋₇ alkyl, OR⁸, or SR⁸;wherein C₁₋₇ alkyl, OR⁸ or SR⁸ of R⁵ can form a ring with any part of X;wherein X is selected from —O—C₁₋₇ alkanediyl, —S—C₁₋₇ alkanediyl, orC₁₋₇ alkanediyl, and wherein —O—C₁₋₇ alkanediyl, —S—C₁₋₇ alkanediyl orC₁₋₇ alkanediyl of X can form a ring with any part of R⁵; and wherein Yis NR¹⁰R¹² wherein R¹⁰ and R¹² can form a ring wherein the ring containsthe N of NR¹⁰R¹² and optionally one further heteroatom selected from Oand N, wherein if the one further heteroatom is N, it is optionallysubstituted by R⁸.
 38. The compound according to any one of the previousclaims, wherein R⁵ is OR⁸, wherein R⁸ of OR⁸ is C₁₋₇ alkyl, and whereinOR⁸ of R⁵ can form a ring with any part of X; wherein X is —O—C₁₋₇alkanediyl and wherein —O—C₁₋₇ alkanediyl of X can form a ring with anypart of R⁵; and wherein Y is NR¹⁰R¹² wherein R¹⁰ and R¹² can form a ringwherein the ring contains the N of NR¹⁰R¹² and four or five carbonatoms.
 39. The compound according to any one of the previous claims,wherein the compound is of any one of Formulae (VIIa), (VIIb), (VIIc),(VIId), (VIIe), or (VIIf):

or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomerthereof, wherein n8 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3,and R¹, R², R³, R⁴, R⁶, R⁷, and R⁸ are as described herein.
 40. Thecompound according to any one of the previous claims, wherein Y is arylor heteroaryl, wherein the aryl or heteroaryl is optionally substitutedby one or more of R⁸; or S-heteroaryl, wherein the S-heteroaryl isoptionally substituted by one or more R¹⁴.
 41. The compound according toany one of the previous claims, wherein R⁵ is selected from H and C₁₋₇alkyl; wherein X is selected from a bond and C₁₋₇ alkanediyl; wherein Yis heteroaryl, wherein the heteroaryl is optionally substituted by oneor more of R⁸; or S-heteroaryl, wherein the S-heteroaryl is optionallysubstituted by one or more R¹⁴.
 42. The compound according to any one ofthe previous claims, wherein Y is C(O)NR¹⁰R¹²; and wherein R¹⁰ and R¹²can form a ring wherein the ring contains the N of NR¹⁰R¹² andoptionally one further heteroatom selected from O and N, wherein if theone further heteroatom is N, it is optionally substituted by R⁸.
 43. Thecompound according to any one of the previous claims, wherein R⁵ isselected from H and C₁₋₇ alkyl; wherein X is selected from a bond andC₁₋₇ alkanediyl; wherein Y is C(O)NR¹⁰R¹²; and wherein R¹⁰ and R¹² canform a ring wherein the ring contains the N of NR¹⁰R¹² and optionallyone further heteroatom selected from O and N, wherein if the one furtherheteroatom is N, it is optionally substituted by R⁸; and wherein R¹⁰ andR¹² are each independently selected from H, C₁₋₇ alkyl, C₂₋₇ alkenyl,C₃₋₇ cycloalkyl, C₁₋₃ alkyl-aryl.
 44. The compound according to any oneof the previous claims, wherein Y is selected from S-aryl, O-aryl,S-heteroaryl, O-heteroaryl, wherein the S-aryl, O-aryl, S-heteroaryl,O-heteroaryl are optionally substituted by one or more R⁹ or R¹⁴. 45.The compound according to any one of the previous claims, wherein R⁵ isselected from H and C₁₋₇ alkyl; wherein X is selected from a bond andC₁₋₇ alkanediyl, wherein Y is selected from O-aryl and O-heteroaryl,wherein the O-aryl or O-heteroaryl is optionally substituted by one ormore R⁹; wherein R⁹ is selected from H, C₁₋₅ alkyl, halogen, C₁₋₅alkyl-NR⁸R¹¹, C₁₋₅ alkyl-C(O)OR⁸, C₁₋₅ alkyl-C(O)NR⁸R¹¹, CN, C(O)R⁸,C(O)NR⁸R¹¹, C(O)OR⁸, and OR⁸.
 46. The compound according to any one ofthe previous claims, wherein Y is C(O)OR¹⁰.
 47. The compound accordingto any one of the previous claims, wherein wherein R⁵ is selected from Hand C₁₋₇ alkyl; wherein X is selected from a bond and C₁₋₇ alkanediyl;wherein Y is C(O)OR¹⁰; and wherein R¹⁰ is selected from H, C₁₋₇ alkyl,C₂₋₇ alkenyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, C₁₋₃ alkanediyl-O—C₁₋₃alkanediyl-O—C₁₋₃ alkanediyl, C₁₋₃ alkyl-aryl, or C₁₋₃ alkyl-heteroaryl,all these groups optionally substituted by OR₈.
 48. The compoundaccording to any one of the previous claims, wherein Y is H.
 49. Thecompound according to any one of the previous claims, wherein wherein R⁵is C₁₋₇ alkyl; wherein X is a bond; and wherein Y is H.
 50. The compoundaccording to any one of the previous claims, wherein Y is CN.
 51. Thecompound according to any one of the previous claims, wherein R⁵ is H; Xis C₁₋₇ alkanediyl; and Y is CN.
 52. The compound according to any oneof the previous claims, wherein the compound is of any one of Formulae(VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh),(VIIIi), (VIIIj), (VIIIk), (VIIIl):

or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomerthereof, wherein Q₁ and Q₂ are each independently O, S, NR⁸, or CR⁸, andR¹, R², R³, R⁴, R⁶, R⁷, R⁸, and Y are as described herein.
 53. Thecompound according to any one of the previous claims, wherein thecompound is of any one of Formulae (IXa), (IXb), (IXc), or (IXd):

or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomerthereof, wherein n10 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or3, and R¹, R², R³, R⁴, R⁶, R⁷, R¹⁰, R¹² and Y are as described herein.54. A compound selected from the group consisting of:


55. A compound selected from the group consisting of:


56. The compound according to any one of the previous claims, whereinthe compound is selected from a compound of any one of Table 2 or Table3.
 57. A pharmaceutical composition comprising a compound according toany one of the previous claims and a pharmaceutically acceptablediluent, excipient or carrier.
 58. The pharmaceutical compositionaccording to claim 57, further comprising an additional pharmaceuticallyactive agent.
 59. The pharmaceutical composition according to claim 58,wherein the additional pharmaceutically active agent comprises anadditional cancer therapy.
 60. The compound according to any one ofclaims 1-56 or the pharmaceutical composition according to claim 57 or58 for use as a medicament.
 61. The compound according to any one ofclaims 1-56 or the or the pharmaceutical composition according to claim57 or 58 for use in a method for preventing or treating cancer in asubject in need thereof.
 62. The compound according to any one of claims1-56 or the pharmaceutical composition according to claim 57 or 58 forthe use in the manufacture of a medicament for the treatment of cancerin a subject in need thereof.
 63. A method of treating cancer in asubject in need thereof, comprising administering to the subject atherapeutically effective amount of a composition comprising thecompound of any one of claims 1-56 or the pharmaceutical composition ofclaim 57 or
 58. 64. The method or composition for use according to anyone of claims 61-63, wherein the cancer comprises a solid tumor or aliquid tumor.
 65. The method or composition for use according to claim64, wherein the solid tumor is a primary tumor or a metastatic tumor.66. The method or composition for use according to claim 64, wherein thesolid tumor is a carcinoma, a sarcoma, a myeloma, a germ cell tumor, acarcinoid tumor, a neuroendocrine tumor or a tumor of mixed type. 67.The method or composition for use according to claim 64, wherein thecancer comprises a lymphoma, a leukemia, a brain cancer, a nervoussystem cancer, a breast cancer, a cervical cancer, an ovarian cancer, acolorectal cancer, a stomach cancer, a gastric cancer, a kidney cancer,a liver cancer, a lung cancer, an oesophageal cancer, a pancreaticcancer, a prostate cancer, a colon cancer, a skin cancer or ahead-and-neck cancer.
 68. The method or composition for use according toclaim 64, wherein the liquid tumor is a leukemia or a lymphoma.
 69. Themethod of composition for use according to any one of claims 61-66,wherein the cancer is Stage I, Stage IIA, Stage IIB, Stage IIIA, StageIIIB, Stage IIIC, or Stage IV cancer.
 70. The method or composition foruse according to any one of claims 61-69, wherein the subject is amouse, a rat, a rabbit, a non-human primate or a human.
 71. The methodor composition for use according to claim 70, wherein the human is achild, an adolescent or an adult.
 72. The method of composition for useaccording to any one of claims 61-71, wherein the compound orpharmaceutical composition is suitable for oral administration.
 73. Themethod of composition for use according to any one of claims 61-71,wherein the compound or pharmaceutical composition is suitable forparenteral administration.
 74. The method or composition for useaccording to claim 73, wherein the parenteral administration comprisessubcutaneous administration, intravenous injection, intravenousinfusion, intraperitoneal injection, intramuscular injection orintratumoral injection.
 75. The method or composition for use accordingto any one of claims 61-74, wherein the method or use of the compositionfurther comprises at least one additional cancer therapy.
 76. The methodor composition for use according to claim 75, wherein the at least oneadditional cancer therapy comprises a standard of care for the cancer.77. The method or composition for use according to claim 75 or 76,wherein the at least one additional cancer therapy comprises surgicalresection of the cancer, radiation therapy, or a combination thereof.78. The method or composition for use according to claim 75, wherein theat least one additional cancer therapy comprises administration of atleast one additional cancer therapeutic agent.
 79. The method orcomposition for use according to claim 78, wherein the administrationcomprises simultaneous administration of the compound or pharmaceuticalcomposition and the at least one additional cancer therapeutic agent.80. The method or composition for use according to claim 79, wherein thecompound or pharmaceutical composition and the at least one additionalcancer therapeutic agent are in the same composition.
 81. The method orcomposition for use according to claim 78, wherein the administrationcomprises administration in temporal proximity of the compound orpharmaceutical composition and the at least one additional cancertherapeutic agent.
 82. The method or composition for use according toclaim 78, wherein the administration comprises sequential administrationof the compound or pharmaceutical composition and the at least oneadditional cancer therapeutic agent.
 83. The method or composition foruse according to any one of claims 78-82, wherein the at least oneadditional cancer therapeutic agent comprises a chemotherapeutic agent.84. The method or composition for use according to claim 83, wherein thechemotherapeutic agent comprises a platinum compound, an alkylatingagent, an antitumor antibiotic, a taxane, an antimetabolite, anucleoside analog, a topoisomerase inhibitor, a hypomethylating agent, aproteasome inhibitor, an epipodophyllotoxin, a DNA synthesis inhibitor,a vinca alkaloid, a tyrosine kinase inhibitor, a nitrosourea,hexamethylmelamine, mitotane, an angiogenesis inhibitor, a steroid, ahormonal agent, an aromatase inhibitor, arsenic trioxide, tretinoin, anonselective cyclooxygenase inhibitor, a selective cyclooxygenase-2(COX-2) inhibitors, or a combination thereof.
 85. The method orcomposition for use according to any one of claims 78-82, wherein the atleast one additional cancer therapeutic agent comprises a biologicalagent.
 86. The method or composition for use according to claim 85,wherein the biological agent comprises an antibody therapy, an adoptivecell therapy, an enzyme, a cytokine, a growth factor, an inhibitor of agrowth factor, a gene therapy a cancer vaccine or a combination thereof.87. The method or composition for use according to claim 86, wherein theantibody therapy comprises ituximab, cetuximab, obinutuzumab,ofatumumab, ibritumomab, brentuximab, bevacizumab, panitumumab,pembrolizumab, tositumomab, trastuzumab, alemtuzumab, gemtuzumabozogamicin, bevacizumab, catumaxomab, denosumab, obinutuzumab,ofatumumab, ramucirumab, pertuzumab, ipilimumab, nivolumab, nimotuzumab,lambrolizumab, pidilizumab, siltuximab, tremelimumab.
 88. The method orcomposition for use according to claim 86, wherein the adoptive celltherapy comprises a chimeric antigen receptor T cell (CAR-T) therapy.89. The method or composition for use according to claim 88, wherein theadoptive cell therapy is autologous or allogeneic.
 90. The method orcomposition for use according to any one of claims 78-82, wherein the atleast one additional cancer therapeutic agent comprises an immunecheckpoint inhibitor.
 91. The method or composition for use according toclaim 90, wherein the immune checkpoint inhibitor comprises nivolumab,pembrolizumab, atezolizumab, avelumab, durvalumab or ipilimumab.
 92. Themethod or composition for use according to claim 86, wherein theantibody therapy comprises a VEGFA antibody.
 93. The method orcomposition for use according to claim 92, wherein the VEGFA antibodycomprises bevacizumab (Avastin®).
 94. The method or composition for useaccording to any one of claims 61-93, wherein the method or use of thecomposition alleviates a sign or a symptom of the cancer.
 95. The methodor composition for use according to claim 94, wherein alleviating a signor a symptom of the cancer comprises a reduction in tumor volume, areduction in tumor size, a reduction in tumor number, a decrease in therate of growth of a tumor or a combination thereof.
 96. A kit,comprising the compound according to any one of claims 1-56 or thepharmaceutical composition according to claim 57 or 58 and instructionsfor use in treating cancer in a subject in need thereof.
 97. The kitaccording to claim 96, further comprising at least one additional cancertherapeutic agent.
 98. The kit according to claim 97, wherein the atleast one additional cancer therapeutic agent comprises achemotherapeutic agent.
 99. The kit according to claim 98, wherein thechemotherapeutic agent comprises a platinum compound, an alkylatingagent, an antitumor antibiotic, a taxane, an antimetabolite, anucleoside analog, a topoisomerase inhibitor, a hypomethylating agent, aproteasome inhibitor, an epipodophyllotoxin, a DNA synthesis inhibitor,a vinca alkaloid, a tyrosine kinase inhibitor, a nitrosourea,hexamethylmelamine, mitotane, an angiogenesis inhibitor, a steroid, ahormonal agent, an aromatase inhibitor, arsenic trioxide, tretinoin, anonselective cyclooxygenase inhibitor, a selective cyclooxygenase-2(COX-2) inhibitors, or a combination thereof.
 100. The kit of claimaccording to claim 97, wherein the at least one additional cancertherapeutic agent comprises a biological agent.
 101. The kit accordingto claim 100, wherein biological agent comprises an antibody therapy, anadoptive cell therapy, an enzyme, a cytokine, a growth factor, aninhibitor of a growth factor, a gene therapy a cancer vaccine or acombination thereof.
 102. The kit according to claim 97, wherein the atleast one additional cancer therapeutic agent comprises an immunecheckpoint inhibitor.
 103. The kit according to claim 102, wherein theimmune checkpoint inhibitor comprises nivolumab, pembrolizumab,atezolizumab, avelumab, durvalumab or ipilimumab.